bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023–05–07
38 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. The Notch signaling pathway: a potential target for cancer immunotherapy.
  2. Reprogramming tumor-associated macrophages as a unique approach to target tumor immunotherapy.
  3. The regulatory network of the chemokine CCL5 in colorectal cancer.
  4. Mechanisms of CD8+ T cell exclusion and dysfunction in cancer resistance to anti-PD-(L)1.
  5. Role of tumor-associated macrophages in common digestive system malignant tumors.
  6. CAA-derived IL-6 induced M2 macrophage polarization by activating STAT3.
  7. The interactions of docetaxel with tumor microenvironment.
  8. Vγ9Vδ2 T-cell immunotherapy in blood cancers: ready for prime time?
  9. Hypoxia-inducible factor orchestrates adenosine metabolism to promote liver cancer development.
  10. RNA Modification in the Immune System.
  11. Target immune components to circumvent sorafenib resistance in hepatocellular carcinoma.
  12. Type 1 interferon mediated signaling is indispensable for eliciting anti-tumor responses by Mycobacterium indicus pranii.
  13. Function and targeting of MALT1 paracaspase in cancer.
  14. Editorial: The role of angiogenesis and immune response in tumor microenvironment of solid tumor.
  15. Knockdown of HMGB1 inhibits the crosstalk between oral squamous cell carcinoma cells and tumor-associated macrophages.
  16. P-Hydroxylcinnamaldehyde induces tumor-associated macrophage polarization toward the M1 type by regulating the proteome and inhibits ESCC in vivo and in vitro.
  17. Epigenetic regulation of cancer-associated fibroblast heterogeneity.
  18. Biomaterials for Chimeric Antigen Receptor T Cell Engineering.
  19. Effects of glycolysis on the polarization and function of tumor‑associated macrophages (Review).
  20. New cell sources for CAR-based immunotherapy.
  21. Immune microenvironment of cholangiocarcinoma: Biological concepts and treatment strategies.
  22. Self-Degradable Nanogels Reshape Immunosuppressive Tumor Microenvironment via Drug Repurposing Strategy to Reactivate Cytotoxic CD8+ T Cells.
  23. Tumor microenvironmental modification by the current target therapy for head and neck squamous cell carcinoma.
  24. Tumor-Specific Peroxynitrite Overproduction Disrupts Metabolic Homeostasis for Sensitizing Melanoma Immunotherapy.
  25. In vitro 3D spheroid model preserves tumor microenvironment of hot and cold breast cancer subtypes.
  26. CHRM4/AKT/MYCN upregulates interferon alpha-17 in the tumor microenvironment to promote neuroendocrine differentiation of prostate cancer.
  27. CD69 on Tumor-Infiltrating Cells Correlates With Neuroblastoma Suppression by Simultaneous PD-1 and PD-L1 Blockade.
  28. Potential functions and therapeutic implications of glioma-resident mesenchymal stem cells.
  29. What is new in cancer-associated fibroblast biomarkers?
  30. Understanding Long-Term Survival of Patients with Ovarian Cancer-The Tumor Microenvironment Comes to the Forefront.
  31. Cancer stem cells: an insight into the development of metastatic tumors and therapy resistance.
  32. Spatial transcriptomics reveals the heterogeneity and FGG+CRP+ inflammatory cancer-associated fibroblasts replace islets in pancreatic ductal adenocarcinoma.
  33. Gene-Expression Profiling to Decipher Breast Cancer Inter- and Intratumor Heterogeneity.
  34. Synergistic effect of CD47 blockade in combination with cordycepin treatment against cancer.
  35. Metabonomic analysis of tumor microenvironments: a mini-review.
  36. NETosis as an oncologic therapeutic target: a mini review.
  37. Molecular, metabolic and functional CD4 T cell paralysis impedes tumor control.
  38. Reprogramming of TAMs via the STAT3/CD47-SIRPα axis promotes acquired resistance to EGFR-TKIs in lung cancer.
  1. J Hematol Oncol. 2023 May 02. 16(1): 45
    The Notch signaling pathway: a potential target for cancer immunotherapy.
    Xinxin Li, Xianchun Yan, Yufeng Wang, Balveen Kaur, Hua Han, Jianhua Yu.
      Dysregulation of the Notch signaling pathway, which is highly conserved across species, can drive aberrant epigenetic modification, transcription, and translation. Defective gene regulation caused by dysregulated Notch signaling often affects networks controlling oncogenesis and tumor progression. Meanwhile, Notch signaling can modulate immune cells involved in anti- or pro-tumor responses and tumor immunogenicity. A comprehensive understanding of these processes can help with designing new drugs that target Notch signaling, thereby enhancing the effects of cancer immunotherapy. Here, we provide an up-to-date and comprehensive overview of how Notch signaling intrinsically regulates immune cells and how alterations in Notch signaling in tumor cells or stromal cells extrinsically regulate immune responses in the tumor microenvironment (TME). We also discuss the potential role of Notch signaling in tumor immunity mediated by gut microbiota. Finally, we propose strategies for targeting Notch signaling in cancer immunotherapy. These include oncolytic virotherapy combined with inhibition of Notch signaling, nanoparticles (NPs) loaded with Notch signaling regulators to specifically target tumor-associated macrophages (TAMs) to repolarize their functions and remodel the TME, combining specific and efficient inhibitors or activators of Notch signaling with immune checkpoint blockers (ICBs) for synergistic anti-tumor therapy, and implementing a customized and effective synNotch circuit system to enhance safety of chimeric antigen receptor (CAR) immune cells. Collectively, this review aims to summarize how Notch signaling intrinsically and extrinsically shapes immune responses to improve immunotherapy.
    Keywords:  Cancer immunotherapy; Chimeric antigen receptor (CAR); Immune cells; Immune checkpoint; Notch signaling; Tumor-associated macrophages
    DOI:  https://doi.org/10.1186/s13045-023-01439-z
  2. Front Immunol. 2023 ;14 1166487
    Reprogramming tumor-associated macrophages as a unique approach to target tumor immunotherapy.
    Safir Ullah Khan, Munir Ullah Khan, Muhammad Azhar Ud Din, Ibrar Muhammad Khan, Muhammad Imran Khan, Simona Bungau, Syed Shams Ul Hassan.
      In the last ten years, it has become increasingly clear that tumor-infiltrating myeloid cells drive not just carcinogenesis via cancer-related inflammatory processes, but also tumor development, invasion, and metastasis. Tumor-associated macrophages (TAMs) in particular are the most common kind of leucocyte in many malignancies and play a crucial role in establishing a favorable microenvironment for tumor cells. Tumor-associated macrophage (TAM) is vital as the primary immune cell subset in the tumor microenvironment (TME).In order to proliferate and spread to new locations, tumors need to be able to hide from the immune system by creating an immune-suppressive environment. Because of the existence of pro-tumoral TAMs, conventional therapies like chemotherapy and radiotherapy often fail to restrain cancer growth. These cells are also to blame for the failure of innovative immunotherapies premised on immune-checkpoint suppression. Understanding the series of metabolic changes and functional plasticity experienced by TAMs in the complex TME will help to use TAMs as a target for tumor immunotherapy and develop more effective tumor treatment strategies. This review summarizes the latest research on the TAMs functional status, metabolic changes and focuses on the targeted therapy in solid tumors.
    Keywords:  Metabolism; anti-cancer treatment; immune suppression; macrophage-targeting immunotherapy; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2023.1166487
  3. Ann Med. 2023 Dec;55(1): 2205168
    The regulatory network of the chemokine CCL5 in colorectal cancer.
    Xin-Feng Zhang, Xiao-Li Zhang, Ya-Jing Wang, Yuan Fang, Meng-Li Li, Xing-Yu Liu, Hua-You Luo, Yan Tian.
      The chemokine CCL5 plays a potential role in the occurrence and development of colorectal cancer (CRC). Previous studies have shown that CCL5 directly acts on tumor cells to change tumor metastatic rates. In addition, CCL5 recruits immune cells and immunosuppressive cells into the tumor microenvironment (TME) and reshapes the TME to adapt to tumor growth or increase antitumor immune efficacy, depending on the type of secretory cells releasing CCL5, the cellular function of CCL5 recruitment, and the underlying mechanisms. However, at present, research on the role played by CCL5 in the occurrence and development of CRC is still limited, and whether CCL5 promotes the occurrence and development of CRC and its role remain controversial. This paper discusses the cells recruited by CCL5 in patients with CRC and the specific mechanism of this recruitment, as well as recent clinical studies of CCL5 in patients with CRC.Key MessagesCCL5 plays dual roles in colorectal cancer progression.CCL5 remodels the tumor microenvironment to adapt to colorectal cancer tumor growth by recruiting immunosuppressive cells or by direct action.CCL5 inhibits colorectal cancer tumor growth by recruiting immune cells or by direct action.
    Keywords:  CCL5; colorectal cancer; immune regulation; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1080/07853890.2023.2205168
  4. Biomed Pharmacother. 2023 May 02. pii: S0753-3322(23)00614-5. [Epub ahead of print]163 114824
    Mechanisms of CD8+ T cell exclusion and dysfunction in cancer resistance to anti-PD-(L)1.
    Keywan Mortaezaee, Jamal Majidpoor.
      CD8+ T cells are the front-line defensive cells against cancer. Reduced infiltration and effector function of CD8+ T cells occurs in cancer and is contributed to defective immunity and immunotherapy resistance. Exclusion and exhaustion of CD8+ T cells are the two key factors associated with reduced durability of immune checkpoint inhibitor (ICI) therapy. Initially activated T cells upon exposure to chronic antigen stimulation or immunosuppressive tumor microenvironment (TME) acquire a hyporesponsive state that progressively lose their effector function. Thus, a key strategy in cancer immunotherapy is to look for factors contributed to defective CD8+ T cell infiltration and function. Targeting such factors can define a promising supplementary approach in patients receiving anti-programmed death-1 receptor (PD-1)/anti-programmed death-ligand 1 (PD-L1) therapy. Recently, bispecific antibodies are developed against PD-(L)1 and a dominant factor within TME, representing higher safety profile and exerting more desired outcomes. The focus of this review is to discuss about promoters of deficient infiltration and effector function of CD8+ T cells and their addressing in cancer ICI therapy.
    Keywords:  CD8(+) T cell; Exhaustion; Immune checkpoint inhibitor (ICI); Programmed death-1 receptor (PD-1); Programmed death-ligand 1 (PD-L1); Resistance
    DOI:  https://doi.org/10.1016/j.biopha.2023.114824
  5. World J Gastrointest Oncol. 2023 Apr 15. 15(4): 596-616
    Role of tumor-associated macrophages in common digestive system malignant tumors.
    Yue Shen, Jia-Xi Chen, Ming Li, Ze Xiang, Jian Wu, Yi-Jin Wang.
      Many digestive system malignant tumors are characterized by high incidence and mortality rate. Increasing evidence has revealed that the tumor microenvironment (TME) is involved in cancer initiation and tumor progression. Tumor-associated macrophages (TAMs) are a predominant constituent of the TME, and participate in the regulation of various biological behaviors and influence the prognosis of digestive system cancer. TAMs can be mainly classified into the antitumor M1 phenotype and protumor M2 phenotype. The latter especially are crucial drivers of tumor invasion, growth, angiogenesis, metastasis, immunosuppression, and resistance to therapy. TAMs are of importance in the occurrence, development, diagnosis, prognosis, and treatment of common digestive system malignant tumors. In this review, we summarize the role of TAMs in common digestive system malignant tumors, including esophageal, gastric, colorectal, pancreatic and liver cancers. How TAMs promote the development of tumors, and how they act as potential therapeutic targets and their clinical applications are also described.
    Keywords:  Clinical applications; Digestive system malignant tumors; Therapeutic targets; Tumor development; Tumor-associated macrophages
    DOI:  https://doi.org/10.4251/wjgo.v15.i4.596
  6. BMC Cancer. 2023 May 01. 23(1): 392
    CAA-derived IL-6 induced M2 macrophage polarization by activating STAT3.
    Chongru Zhao, Ning Zeng, Xiaomei Zhou, Yufang Tan, Yichen Wang, Jun Zhang, Yiping Wu, Qi Zhang.
       BACKGROUND: Tumor-associated macrophages (TAMs) are the most abundant types of immune cells in the tumor microenvironment (TME) of breast cancer (BC). TAMs usually exhibit an M2 phenotype and promote tumor progression by facilitating immunosuppression. This study aimed to investigate the effect of CAA-derived IL-6 on macrophage polarization in promoting BC progression.
    METHODS: Human BC samples and adipocytes co-cultured with 4T1 BC cells were employed to explore the properties of CAAs. The co-implantation of adipocytes and 4T1 cells in mouse tumor-bearing model and tail vein pulmonary metastasis model were constructed to investigate the impact of CAAs on BC malignant progression in vivo. The functional assays, qRT-PCR, western blotting assay and ELISA assay were employed to explore the effect of CAA-derived IL-6 on macrophage polarization and programmed cell death protein ligand 1 (PD-L1) expression.
    RESULTS: CAAs were located at the invasive front of BC and possessed a de-differentiated fibroblast phenotype. CAAs facilitated the malignant behaviors of 4T1 cells in vitro, and promoted 4T1 tumor growth and pulmonary metastasis in vivo. The IHC staining of both human BC specimens and xenograft and the in vitro experiment indicated that CAAs could enhance infiltration of M2 macrophages in the TME of 4T1 BC. Furthermore, CAA-educated macrophages could enhance malignant behaviors of 4T1 cells in vitro. More importantly, CAAs could secret abundant IL-6 and thus induce M2 macrophage polarization by activating STAT3. In addition, CAAs could upregulate PD-L1 expression in macrophages.
    CONCLUSIONS: Our study revealed that CAAs and CAA-educated macrophages enhanced the malignant behaviors of BC. Specifically, CAA-derived IL-6 induced migration and M2 polarization of macrophages via activation STAT3 and promoted macrophage PD-L1 expression, thereby leading to BC progression.
    Keywords:  Breast cancer; Cancer-associated adipocytes; IL-6; Macrophages; STAT3
    DOI:  https://doi.org/10.1186/s12885-023-10826-1
  7. Int Immunopharmacol. 2023 Apr 29. pii: S1567-5769(23)00535-0. [Epub ahead of print]119 110214
    The interactions of docetaxel with tumor microenvironment.
    Reena Gupta, Mustafa M Kadhim, Abduladheem Turki Jalil, Mohammed Qasim Alasheqi, Fahad Alsaikhan, Nurkhan Khalimovna Mukhamedova, Andrés Alexis Ramírez-Coronel, Zanko Hassan Jawhar, Pushpamala Ramaiah, Masoud Najafi.
      There are several interactions within the tumor microenvironment (TME) that affect the response of cancer cells to therapy. There are also a large number of cells and secretions in TME that increase resistance to therapy. Following the release of immunosuppressive, pro-angiogenic, and metastatic molecules by certain cells such as tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and cancer cells, immune evasion, angiogenesis, and metastasis may be induced. However, natural killer (NK) cells and cytotoxic CD8 + T lymphocytes (CTLs) can responsively release anticancer molecules. In addition, anticancer drugs can modulate these cells and their interactions in favor of either cancer resistance or therapy. Docetaxel belongs to taxanes, a class of anti-tumor drugs, which acts through the polymerization of tubulin and the induction of cell cycle arrest. Also, it has been revealed that taxanes including docetaxel affect cancer cells and the other cells within TME through some other mechanisms such as modulation of immune system responses, angiogenesis, and metastasis. In this paper, we explain the basic mechanisms of docetaxel interactions with malignant cells. Besides, we review the diverse effects of docetaxel on TME and cancer cells in consequence. Lastly, the modulatory effects of docetaxel alone or in conjunction with other anticancer agents on anti-tumor immunity, cancer cell resistance, angiogenesis, and metastasis will be discussed.
    Keywords:  Angiogenesis; Cancer; Docetaxel; Immune system; Tumor Microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.intimp.2023.110214
  8. Front Immunol. 2023 ;14 1167443
    Vγ9Vδ2 T-cell immunotherapy in blood cancers: ready for prime time?
    Claudia Giannotta, Federica Autino, Massimo Massaia.
      In the last years, the tumor microenvironment (TME) has emerged as a promising target for therapeutic interventions in cancer. Cancer cells are highly dependent on the TME to growth and evade the immune system. Three major cell subpopulations are facing each other in the TME: cancer cells, immune suppressor cells, and immune effector cells. These interactions are influenced by the tumor stroma which is composed of extracellular matrix, bystander cells, cytokines, and soluble factors. The TME can be very different depending on the tissue where cancer arises as in solid tumors vs blood cancers. Several studies have shown correlations between the clinical outcome and specific patterns of TME immune cell infiltration. In the recent years, a growing body of evidence suggests that unconventional T cells like natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) cells, and γδ T cells are key players in the protumor or antitumor TME commitment in solid tumors and blood cancers. In this review, we will focus on γδ T cells, especially Vγ9Vδ2 T cells, to discuss their peculiarities, pros, and cons as potential targets of therapeutic interventions in blood cancers.
    Keywords:  Vγ9Vδ2 T cells; adoptive cell transfer; blood cancers; immunotherapy; unconventional T cells
    DOI:  https://doi.org/10.3389/fimmu.2023.1167443
  9. Sci Adv. 2023 May 05. 9(18): eade5111
    Hypoxia-inducible factor orchestrates adenosine metabolism to promote liver cancer development.
    Jacinth Wing-Sum Cheu, David Kung-Chun Chiu, Kenneth Kin-Leung Kwan, Chunxue Yang, Vincent Wai-Hin Yuen, Chi Ching Goh, Noreen Nog-Qin Chui, Wei Shen, Cheuk-Ting Law, Qidong Li, Misty Shuo Zhang, Macus Hao-Ran Bao, Bowie Po-Yee Wong, Cerise Yuen-Ki Chan, Cindy Xinqi Liu, Grace Fu-Wan Sit, Zher Yee Ooi, Haijing Deng, Aki Pui-Wah Tse, Irene Oi-Lin Ng, Carmen Chak-Lui Wong.
      Hypoxia-induced adenosine creates an immunosuppressive tumor microenvironment (TME) and dampens the efficacy of immune checkpoint inhibitors (ICIs). We found that hypoxia-inducible factor 1 (HIF-1) orchestrates adenosine efflux through two steps in hepatocellular carcinoma (HCC). First, HIF-1 activates transcriptional repressor MXI1, which inhibits adenosine kinase (ADK), resulting in the failure of adenosine phosphorylation to adenosine monophosphate. This leads to adenosine accumulation in hypoxic cancer cells. Second, HIF-1 transcriptionally activates equilibrative nucleoside transporter 4, pumping adenosine into the interstitial space of HCC, elevating extracellular adenosine levels. Multiple in vitro assays demonstrated the immunosuppressive role of adenosine on T cells and myeloid cells. Knockout of ADK in vivo skewed intratumoral immune cells to protumorigenic and promoted tumor progression. Therapeutically, combination treatment of adenosine receptor antagonists and anti-PD-1 prolonged survival of HCC-bearing mice. We illustrated the dual role of hypoxia in establishing an adenosine-mediated immunosuppressive TME and offered a potential therapeutic approach that synergizes with ICIs in HCC.
    DOI:  https://doi.org/10.1126/sciadv.ade5111
  10. Annu Rev Immunol. 2023 04 26. 41 73-98
    RNA Modification in the Immune System.
    Dali Han, Meng Michelle Xu.
      Characterization of RNA modifications has identified their distribution features and molecular functions. Dynamic changes in RNA modification on various forms of RNA are essential for the development and function of the immune system. In this review, we discuss the value of innovative RNA modification profiling technologies to uncover the function of these diverse, dynamic RNA modifications in various immune cells within healthy and diseased contexts. Further, we explore our current understanding of the mechanisms whereby aberrant RNA modifications modulate the immune milieu of the tumor microenvironment and point out outstanding research questions.
    Keywords:  N6-methyladenosine; RNA modification; antitumor immunity; antiviral immunity; epitranscriptome; tumor microenvironment
    DOI:  https://doi.org/10.1146/annurev-immunol-101921-045401
  11. Biomed Pharmacother. 2023 Apr 28. pii: S0753-3322(23)00588-7. [Epub ahead of print]163 114798
    Target immune components to circumvent sorafenib resistance in hepatocellular carcinoma.
    Shuhua Wei, Fenghua Wei, Mengyuan Li, Yuhan Yang, Jingwen Zhang, Chunxiao Li, Junjie Wang.
      Sorafenib, a multi-kinase inhibitor, has been approved for cancer treatment for decades, especially hepatocellular carcinoma (HCC). Although sorafenib produced substantial clinical benefits in the initial stage, a large proportion of cancer patients acquired drug resistance in subsequent treatment, which always disturbs clinical physicians. Cumulative evidence unraveled the underlying mechanism of sorafenib, but few reports focused on the role of immune subpopulations, since the immunological rationale of sorafenib resistance has not yet been defined. Here, we reviewed the immunoregulatory effects of sorafenib on the tumor microenvironment and emphasized the potential immunological mechanisms of therapeutic resistance to sorafenib. Moreover, we also summarized the clinical outcomes and ongoing trials in combination of sorafenib with immunotherapy, highlighted the immunotherapeutic strategies to improve sorafenib efficacy, and put forward several prospective questions aimed at guiding future research in overcoming sorafenib resistance in HCC.
    Keywords:  Drug resistance; Hepatocellular carcinoma; Immune cells; Sorafenib; Therapeutic strategies; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.biopha.2023.114798
  12. Front Immunol. 2023 ;14 1104711
    Type 1 interferon mediated signaling is indispensable for eliciting anti-tumor responses by Mycobacterium indicus pranii.
    Gargi Roy, Anush Chakraborty, Bharati Swami, Lalit Pal, Charvi Ahuja, Soumen Basak, Sangeeta Bhaskar.
       Introduction: The evolving tumor secretes various immunosuppressive factors that reprogram the tumor microenvironment (TME) to become immunologically cold. Consequently, various immunosuppressive cells like Tregs are recruited into the TME which in turn subverts the anti-tumor response of dendritic cells and T cells.Tumor immunotherapy is a popular means to rejuvenate the immunologically cold TME into hot. Mycobacterium indicus pranii (MIP) has shown strong immunomodulatory activity in different animal and human tumor models and has been approved for treatment of lung cancer (NSCLC) patients as an adjunct therapy. Previously, MIP has shown TLR2/9 mediated activation of antigen presenting cells/Th1 cells and their enhanced infiltration in mouse melanoma but the underlying mechanism by which it is modulating these immune cells is not yet known.
    Results: This study reports for the first time that MIP immunotherapy involves type 1 interferon (IFN) signaling as one of the major signaling pathways to mediate the antitumor responses. Further, it was observed that MIP therapy significantly influenced frequency and activation of different subsets of T cells like regulatory T cells (Tregs) and CD8+ T cells in the TME. It reduces the migration of Tregs into the TME by suppressing the expression of CCL22, a Treg recruiting chemokine on DCs and this process is dependent on type 1 IFN. Simultaneously, in a type 1 IFN dependent pathway, it enhances the activation and effector function of the immunosuppressive tumor resident DCs which in turn effectively induce the proliferation and effector function of the CD8+ T cells.
    Conclusion: This study also provides evidence that MIP induced pro-inflammatory responses including induction of effector function of conventional dendritic cells and CD8+ T cells along with reduction of intratumoral Treg frequency are essentially mediated in a type 1 IFN-dependent pathway.
    Keywords:  CD8+ T cells; Mycobacterium indicus pranii; dendritic cells; regulatory T cells; tumor immunotherapy; type 1 interferon signaling
    DOI:  https://doi.org/10.3389/fimmu.2023.1104711
  13. Cancer Treat Rev. 2023 Apr 26. pii: S0305-7372(23)00059-2. [Epub ahead of print]117 102568
    Function and targeting of MALT1 paracaspase in cancer.
    Thomas J O'Neill, Marie J Tofaute, Daniel Krappmann.
      The paracaspase MALT1 has emerged as a key regulator of immune signaling, which also promotes tumor development by both cancer cell-intrinsic and -extrinsic mechanisms. As an integral subunit of the CARD11-BCL10-MALT1 (CBM) signaling complex, MALT1 has an intriguing dual function in lymphocytes. MALT1 acts as a scaffolding protein to drive activation of NF-κB transcription factors and as a protease to modulate signaling and immune activation by cleavage of distinct substrates. Aberrant MALT1 activity is critical for NF-κB-dependent survival and proliferation of malignant cancer cells, which is fostered by paracaspase-catalyzed inactivation of negative regulators of the canonical NF-κB pathway like A20, CYLD and RelB. Specifically, B cell receptor-addicted lymphomas rely strongly on this cancer cell-intrinsic MALT1 protease function, but also survival, proliferation and metastasis of certain solid cancers is sensitive to MALT1 inhibition. Beyond this, MALT1 protease exercises a cancer cell-extrinsic role by maintaining the immune-suppressive function of regulatory T (Treg) cells in the tumor microenvironment (TME). MALT1 inhibition is able to convert immune-suppressive to pro-inflammatory Treg cells in the TME of solid cancers, thereby eliciting a robust anti-tumor immunity that can augment the effects of checkpoint inhibitors. Therefore, the cancer cell-intrinsic and -extrinsic tumor promoting MALT1 protease functions offer unique therapeutic opportunities, which has motivated the development of potent and selective MALT1 inhibitors currently under pre-clinical and clinical evaluation.
    Keywords:  Anti-tumor immunity; CBM complex; Cancer therapy; Lymphoma; MALT1; Precision medicine
    DOI:  https://doi.org/10.1016/j.ctrv.2023.102568
  14. Front Immunol. 2023 ;14 1195390
    Editorial: The role of angiogenesis and immune response in tumor microenvironment of solid tumor.
    Zichao Guo, Yimei Jiang, Baochi Ou, Xin Lu, Xi Cheng, Ren Zhao.
      
    Keywords:  angiogenesis and antiangiogenetic therapy; tumor immune infiltration; tumor immunotherapy; tumor microenvironment; tumor treatment and prognostic prediction
    DOI:  https://doi.org/10.3389/fimmu.2023.1195390
  15. Int Immunopharmacol. 2023 May 02. pii: S1567-5769(23)00580-5. [Epub ahead of print]119 110259
    Knockdown of HMGB1 inhibits the crosstalk between oral squamous cell carcinoma cells and tumor-associated macrophages.
    Jinlin Wen, Panpan Yin, Ying Su, Feng Gao, Yanlin Wu, Wenbin Zhang, Peng Chi, Jiahui Chen, Xinyan Zhang.
      Tumor-associated macrophages (TAMs), the major component of the tumor microenvironment (TME), play distinctly different roles in different tumors. High mobility group box 1 (HMGB1), a nonhistone protein in the nucleus, can perform functions during inflammation and cancers. However, the role of HMGB1 in the crosstalk between oral squamous cell carcinoma (OSCC) cells and TAMs remains unclear. Here, we established a coculture system of TAMs and OSCC cells to explore the bidirectional effect and potential mechanism of HMGB1 in OSCC cell-TAM interactions. Our results showed that HMGB1 was significantly upregulated in OSCC tissues and positively associated with tumor progression, immune cell infiltration and macrophage polarization. Then, knocking down HMGB1 in OSCC cells inhibited the recruitment and polarization of cocultured TAMs. Moreover, the knockdown of HMGB1 in macrophages not only suppressed polarization, but also inhibited cocultured OSCC cell proliferation, migration and invasion in vitro and in vivo. Mechanistically, macrophages secreted higher levels of HMGB1 than OSCC cells, and dampening endogenous HMGB1 reduced HMGB1 secretion. Both OSCC cell-generated and macrophage-endogenous HMGB1 may regulate TAM polarization by promoting receptor TLR4 expression and NF-κB/p65 activation and enhancing IL-10/TGF-β expression. HMGB1 in OSCC cells may regulate macrophage recruitment via IL-6/STAT3. In addition, TAM-derived HMGB1 may affect aggressive phenotypes of cocultured OSCC cells by regulating the immunosuppressive microenvironment through the IL-6/STAT3/PD-L1 and IL-6/NF-κB/MMP-9 pathways. In conclusion, HMGB1 may regulate the crosstalk between OSCC cells and TAMs, including modulating macrophage polarization and attraction, enhancing cytokine secretion, and remodeling and creating an immunosuppressive TME to further affect OSCC progression.
    Keywords:  Crosstalk; HMGB1; Metastasis; OSCC; TAMs; TME
    DOI:  https://doi.org/10.1016/j.intimp.2023.110259
  16. Int Immunopharmacol. 2023 May 01. pii: S1567-5769(23)00534-9. [Epub ahead of print]119 110213
    P-Hydroxylcinnamaldehyde induces tumor-associated macrophage polarization toward the M1 type by regulating the proteome and inhibits ESCC in vivo and in vitro.
    Xiaohan Wang, Sisi Wei, Wanzhao Li, Xiaojian Wei, Cong Zhang, Suli Dai, Ming Ma, Lianmei Zhao, Baoen Shan.
      P-Hydroxylcinnamaldehyde (CMSP) was firstly isolated from Chinese medicine Cochinchinnamomordica seed (CMS) by our team and has been verified to have growth-inhibiting abilities in malignant tumors including esophageal squamous cell carcinoma (ESCC). However, the detailed mechanism of its function is still unclear. Tumor-associated macrophages (TAMs) are an essential component of the tumor microenvironment (TME), playing important roles in tumor growth, metastasis, angiogenesis, and epithelial-mesenchymal transition (EMT). In the present study, we found that the percentage of M1-like macrophages was significantly increased in TME of ESCC cell derivedxenograft tumor model after CMSP treatment, while the ratios of other immune cells showed relatively low variation. To confirm these results, we further examined the effect of CMSP on macrophage polarization in vitro. The results revealed that CMSP also could induce phorbol-12-myristate-13-acetate (PMA)-induced M0 macrophages from THP-1 and mouse peritoneal macrophages toward the M1-like macrophages. Furthermore, CMSP could exert anti-tumor effect through TAMs in vitro co-culture model, in addition, the growth inhibition effect of CMSP was partly abolished in macrophage depletion model. To determine the potential pathway of CMSP induced polarization, we used quantitative proteomics (label-free) technology to explore the proteomic changes under CMSP treatment. The results revealed that immune-activating protein and M1 macrophage biomarkers were significantly increased after CMSP treatment. More importantly, CMSP stimulated pathways related to M1 macrophage polarization, such as the NF-κB signaling pathway and Toll-like receptor pathway, indicating that CMSP might induce M1-type macrophage polarization through these pathways. In conclusion, CMSP can regulate immune microenvironment in vivo and induce TAM polarization toward the M1 type by promoting proteomic changes, and exert anti-tumor effect through TAMs.
    Keywords:  Esophageal squamous cell carcinoma; Polarization; Proteomics; Tumor-associated macrophages; p-Hydroxylcinnamaldehyde (CMSP)
    DOI:  https://doi.org/10.1016/j.intimp.2023.110213
  17. Biochim Biophys Acta Rev Cancer. 2023 Apr 27. pii: S0304-419X(23)00050-1. [Epub ahead of print] 188901
    Epigenetic regulation of cancer-associated fibroblast heterogeneity.
    Rachel J Kehrberg, Namita Bhyravbhatla, Surinder K Batra, Sushil Kumar.
      Cancer-associated fibroblasts (CAFs), a significant component of the tumor microenvironment (TME), contribute to cancer progression through the secretion of extracellular matrix (ECM), growth factors, and metabolites. It is now well recognized that CAFs are a heterogenous population with ablation experiments leading to reduced tumor growth and single-cell RNA sequencing demonstrating CAF subgroups. CAFs lack genetic mutations yet substantially differ from their normal stromal precursors. Here, we review epigenetic changes in CAF maturation, focusing on DNA methylation and histone modifications. DNA methylation changes in CAFs have been demonstrated globally, while roles of methylation at specific genes affect tumor growth. Further, loss of CAF histone methylation and gain of histone acetylation has been shown to promote CAF activation and tumor promotion. Many CAF activating factors, such as transforming growth factor β (TGFβ), lead to these epigenetic changes. MicroRNAs (miRNAs) serve as targets and orchestrators of epigenetic modifications that influence gene expression. Bromodomain and extra-terminal domain (BET), an epigenetic reader, recognizes histone acetylation and activates the transcription of genes leading to the pro-tumor phenotype of CAFs.
    Keywords:  Cancer-associated fibroblasts; DNA methylation; Epigenetics; Histone acetylation; Histone methylation; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2023.188901
  18. Acta Biomater. 2023 May 01. pii: S1742-7061(23)00243-X. [Epub ahead of print]
    Biomaterials for Chimeric Antigen Receptor T Cell Engineering.
    Huanqing Niu, Penghui Zhao, Wujin Sun.
      Chimeric antigen receptor T (CAR-T) cells have achieved breakthrough efficacies against hematological malignancies, but their unsatisfactory efficacies in solid tumors limit their applications. The prohibitively high prices further restrict their access to broader populations. Novel strategies are urgently needed to address these challenges, and engineering biomaterials can be one promising approach. The established process for manufacturing CAR-T cells involves multiple steps, and biomaterials can help simplify or improve several of them. In this review, we cover recent progress in engineering biomaterials for producing or stimulating CAR-T cells. We focus on the engineering of non-viral gene delivery nanoparticles for transducing CAR into T cells ex vivo/in vitro or in vivo. We also dive into the engineering of nano-/microparticles or implantable scaffolds for local delivery or stimulation of CAR-T cells. These biomaterial-based strategies can potentially change the way CAR-T cells are manufactured, significantly reducing their cost. Modulating the tumor microenvironment with the biomaterials can also considerably enhance the efficacy of CAR-T cells in solid tumors. We pay special attention to progress made in the past five years, and perspectives on future challenges and opportunities are also discussed. STATEMENT OF SIGNIFICANCE: Chimeric antigen receptor T (CAR-T) cell therapies have revolutionized the field of cancer immunotherapy with genetically engineered tumor recognition. They are also promising for treating many other diseases. However, the widespread application of CAR-T cell therapy has been hampered by the high manufacturing cost. Poor penetration of CAR-T cells into solid tissues further restricted their use. While biological strategies have been explored to improve CAR-T cell therapies, such as identifying new cancer targets or integrating smart CARs, biomaterial engineering provides alternative strategies toward better CAR-T cells. In this review, we summarize recent advances in engineering biomaterials for CAR-T cell improvement. Biomaterials ranging from nano-, micro-, and macro-scales have been developed to assist CAR-T cell manufacturing and formulation.
    Keywords:  Chimeric antigen receptor T cell therapy; Implantable scaffolds; Nano-/microparticles; Non-viral transduction
    DOI:  https://doi.org/10.1016/j.actbio.2023.04.043
  19. Int J Oncol. 2023 Jun;pii: 70. [Epub ahead of print]62(6):
    Effects of glycolysis on the polarization and function of tumor‑associated macrophages (Review).
    Jiaying Cao, Feng Zeng, Shan Liao, Lan Cao, Yanhong Zhou.
      Under conditions of oxygen sufficiency, tumor cells supply themselves with energy through glycolysis, which is one of the causes of their rapid proliferation, metastasis and acquisition of drug resistance. Tumor‑associated macrophages (TAMs) are transformed from peripheral blood monocytes and are among the immune‑related cells that constitute the tumor microenvironment (TME). Altered glycolysis levels in TAMs have an important impact on their polarization and function. The cytokines secreted by TAMs, and phagocytosis in different polarization states, affect tumorigenesis and development. Furthermore, changes in glycolysis activity of tumor cells and other immune‑related cells in the TME also affect the polarization and function of TAMs. Studies on the relationship between glycolysis and TAMs have received increasing attention. The present study summarized the link between glycolysis of TAMs and their polarization and function, as well as the interaction between changes in glycolysis of tumor cells and other immune‑associated cells in the TME and TAMs. The present review aimed to provide a comprehensive understanding of the effects of glycolysis on the polarization and function of TAMs.
    Keywords:  function; glycolysis; polarization; tumor microenvironment; tumor‑associated macrophages
    DOI:  https://doi.org/10.3892/ijo.2023.5518
  20. Biomark Res. 2023 May 06. 11(1): 49
    New cell sources for CAR-based immunotherapy.
    Marzieh Mazinani, Fatemeh Rahbarizadeh.
      Chimeric antigen receptor (CAR) T cell therapy, in which a patient's own T lymphocytes are engineered to recognize and kill cancer cells, has achieved striking success in some hematological malignancies in preclinical and clinical trials, resulting in six FDA-approved CAR-T products currently available in the market. Despite impressive clinical outcomes, concerns about treatment failure associated with low efficacy or high cytotoxicity of CAR-T cells remain. While the main focus has been on improving CAR-T cells, exploring alternative cellular sources for CAR generation has garnered growing interest. In the current review, we comprehensively evaluated other cell sources rather than conventional T cells for CAR generation.
    Keywords:  Chimeric antigen receptors; Hematopoietic stem/progenitor cells; Induced pluripotent stem cells; Macrophages; Mucosal-associated invariant T cells; Natural killer T cells; Natural killer cells; Neutrophils; Regulatory T cells; γδT cells
    DOI:  https://doi.org/10.1186/s40364-023-00482-9
  21. Front Immunol. 2023 ;14 1037945
    Immune microenvironment of cholangiocarcinoma: Biological concepts and treatment strategies.
    Xianzhe Yu, Lingling Zhu, Ting Wang, Jiang Chen.
      Cholangiocarcinoma is characterized by a poor prognosis with limited treatment and management options. Chemotherapy using gemcitabine with cisplatin is the only available first-line therapy for patients with advanced cholangiocarcinoma, although it offers only palliation and yields a median survival of < 1 year. Recently there has been a resurgence of immunotherapy studies focusing on the ability of immunotherapy to inhibit cancer growth by impacting the tumor microenvironment. Based on the TOPAZ-1 trial, the US Food and Drug Administration has approved the combination of durvalumab and gemcitabine with cisplatin as the first-line treatment of cholangiocarcinoma. However, immunotherapy, like immune checkpoint blockade, is less effective in cholangiocarcinoma than in other types of cancer. Although several factors such as the exuberant desmoplastic reaction are responsible for cholangiocarcinoma treatment resistance, existing literature on cholangiocarcinoma cites the inflammatory and immunosuppressive environment as the most common factor. However, mechanisms activating the immunosuppressive tumor microenvironment contributing to cholangiocarcinoma drug resistance are complicated. Therefore, gaining insight into the interplay between immune cells and cholangiocarcinoma cells, as well as the natural development and evolution of the immune tumor microenvironment, would provide targets for therapeutic intervention and improve therapeutic efficacy by developing multimodal and multiagent immunotherapeutic approaches of cholangiocarcinoma to overcome the immunosuppressive tumor microenvironment. In this review, we discuss the role of the inflammatory microenvironment-cholangiocarcinoma crosstalk and reinforce the importance of inflammatory cells in the tumor microenvironment, thereby highlighting the explanatory and therapeutic shortcomings of immunotherapy monotherapy and proposing potentially promising combinational immunotherapeutic strategies.
    Keywords:  cholangiocarcinoma; immune checkpoint blockade; immunosuppressive; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1037945
  22. Adv Sci (Weinh). 2023 May 05. e2301661
    Self-Degradable Nanogels Reshape Immunosuppressive Tumor Microenvironment via Drug Repurposing Strategy to Reactivate Cytotoxic CD8+ T Cells.
    Hao Tian, Wenxi Li, Guohao Wang, Ye Tian, Jie Yan, Songtao Zhou, Xinying Yu, Bei Li, Yunlu Dai.
      Intratumoral CD8+  T cells are crucial for effective cancer immunotherapy, but an immunosuppressive tumor microenvironment (TME) contributes to dysfunction and insufficient infiltration. Drug repurposing has successfully led to new discoveries among existing clinical drugs for use as immune modulators to ameliorate immunosuppression in TME and reactivate T-cell-mediated antitumor immunity. However, due to suboptimal tumor bioavailability, the full potential of immunomodulatory effects of these old drugs has not been realized. The self-degradable PMI nanogels carrying two repurposed immune modulators, imiquimod (Imi) and metformin (Met), are reported for TME-responsive drug release. It remodels the TME through the following aspects: 1) promoting dendritic cells maturation, 2) repolarizing M2-like tumor-associated macrophages, and 3) downregulating PD-L1 expression. Ultimately, PMI nanogels reshaped the immunosuppressive TME and efficiently promote CD8+ T cell infiltration and activation. These results support that PMI nanogels can potentially be an effective combination drug for enhancing the antitumor immune response of anti-PD-1 antibodies.
    Keywords:  CD8+ T cells; drug repurposing; immunosuppressive tumor microenvironment; self-degradable nanogels
    DOI:  https://doi.org/10.1002/advs.202301661
  23. J Exp Clin Cancer Res. 2023 May 05. 42(1): 114
    Tumor microenvironmental modification by the current target therapy for head and neck squamous cell carcinoma.
    Kohei Okuyama, Tomofumi Naruse, Souichi Yanamoto.
      Current clinical and observational evidence supports the EXTREME regimen as one of the standards of care for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) followed by the administration of immune checkpoint inhibitors (ICIs). In addition to the inhibition of the epidermal growth factor receptor (EGFR) pathway, cetuximab-mediated EGFR blockade has been shown to modulate tumor microenvironment (TME) characteristics, such as antibody-dependent cellular cytotoxicity (ADCC) activity, cytotoxic T-lymphocyte (CTL) infiltration into the tumor, anti-angiogenesis activity, and cytokine secretion via associated natural killer (NK) cells, etc.. On the other hand, there are reports that nivolumab affects the TME via Programmed cell death 1 (PD-1) inhibition, Interleukin-10 upregulation via T-cells, myeloid-derived suppressor cell-mediated immune escape induction, and tumor vessel perfusion by promoting CD8 + T-cell accumulation and Interferon-γ production in treatment-sensitive tumor cells. Actually, nivolumab administration can give T cells in the TME both immune superiority and inferiority. HNSCC treatment using cetuximab increases the frequency of FoxP3 + intratumoral effector regulatory T cells (Tregs) expressing CTL associated antigen (CTLA)-4, and targeting CTLA-4 + Tregs using ipilimumab restores the cytolytic function of NK cells, which mediate ADCC activity. Treg-mediated immune suppression also contributes to clinical response to cetuximab treatment, suggesting the possibility of the addition of ipilimumab or the use of other Treg ablation strategies to promote antitumor immunity. Moreover, also in hyper progression disease (HPD), intratumoral frequency of FoxP3 + effector Tregs expressing CTLA-4 is increased. Therefore, combination treatment with cetuximab plus anti-CTLA-4 antibody ipilimumab for HNSCC and this combination therapy after nivolumab administration for HPD may be expected to result in a higher tumor-control response. Based on the above evidence, we here suggest the efficacy of using these therapeutic strategies for patients with local-advanced, recurrent, and metastatic HNSCC and patients who do not respond well to nivolumab administration.
    Keywords:  CTLA-4; Cetuximab; Head and neck squamous cell carcinoma; Immune checkpoint inhibitors; Nivolumab; PD-1; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13046-023-02691-4
  24. Adv Mater. 2023 May 03. e2301455
    Tumor-Specific Peroxynitrite Overproduction Disrupts Metabolic Homeostasis for Sensitizing Melanoma Immunotherapy.
    Lijun Yang, Dianyu Wang, Haixue Jia, Cuihong Yang, Yumin Zhang, Hui Li, Jinjian Liu, Jianfeng Liu.
      Tumor cells elicit metabolic reprogramming to establish an immunosuppressive tumor microenvironment (TME) for escaping from immunosurveillance. Therefore, interrupting the metabolic adaption of tumor cells might be a promising strategy for TME immunomodulation, favoring immunotherapy. Herein, w e construct a tumor-specific ONOO- nanogenerator (APAP-P-NO) that can selectively disrupt metabolic homeostasis in melanoma cells. Stimulated by melanoma-characteristic acid, glutathione, and tyrosinase, APAP-P-NO could efficiently generate ONOO- through the in situ coupling of the produced O2 •- and released NO. Metabolomics profiling reveals that the accumulated ONOO- induces great decrease of metabolites involved in the TCA cycle. Meanwhile, the aerobic glycolysis-produced lactate drops sharply both intracellularly and extracellularly under ONOO- stress. Mechanistically, ONOO- impairs the activity of glyceraldehyde-3-phosphate dehydrogenase in glucose metabolism through S-nitrosylation. The metabolic alterations effectively reverse the immunosuppressive TME to evoke potent antitumor immune responses, including polarization of M2-like macrophages to M1 phenotype, reduction of myeloid-derived suppressor cells and regulatory T cells, and restoration of CD8+ T cell infiltration. Combining APAP-P-NO pretreatment with anti-PD-L1 achieves a significant inhibition against both primary and metastatic melanomas without systemic toxicities. Collectively, w e develop a tumor-specific ONOO- overproduction approach and explore the possible mechanism of ONOO- -mediated TME immunomodulation, providing a new strategy for facilitating immunotherapy sensitivity. This article is protected by copyright. All rights reserved.
    Keywords:  TME immunomodulation; immunotherapy; metabolic homeostasis disruption; peroxynitrite; self-assembling peptide
    DOI:  https://doi.org/10.1002/adma.202301455
  25. Adv Healthc Mater. 2023 May 04. e2300164
    In vitro 3D spheroid model preserves tumor microenvironment of hot and cold breast cancer subtypes.
    Hemavathi Dhandapani, Armaan Siddiqui, Shivam Karadkar, Prakriti Tayalia.
      Dynamic interaction of cancer, immune and stromal cells with extracellular matrix components modulates and resists the response of standard care therapies. To mimic this, we designed an in vitro three-dimensional (3D) spheroid model using liquid overlay method to simulate hot (MDA-MB-231) and cold (MCF-7) breast tumor microenvironment (TME). Our study shows increased mesenchymal phenotype, stemness and suppressive microenvironment in MDA-MB-231-spheroids upon exposure to doxorubicin. Intriguingly, presence of human dermal fibroblasts enhances cancer-associated fibroblast (CAF) phenotype in MDA-MB-231-spheroids through increased expression of CXCL12 and FSP-1, leading to higher infiltration of immune cells (THP-1 monocytes). However, a suppressive TME was observed in both subtypes, as seen by upregulation of M2-macrophage specific CD68 and CD206 markers. Specifically, increased PDL-1 expressing tumor associated macrophages (TAMs) along with FoxP3 expressing T regulatory (T-regs) cells were found in MDA-MB-231-spheroids when cultured with peripheral blood mononuclear cells (PBMCs). Further, we found that addition of 1-methyl-tryptophan, a potent indoleamine-2,3-dioxygenase-1 (IDO-1) inhibitor, subsided the suppressive phenotype by decreasing the M2 polarisation via downregulation of tryptophan metabolism and IL10 expression, particularly in MCF-7 triculture spheroids. Thus, our in vitro 3D spheroid model of TME can be utilized in therapeutics to validate immunomodulatory drugs for various breast cancer subtypes. This article is protected by copyright. All rights reserved.
    Keywords:  CAFs; MCF-7; MDA-MB-231; PDL-1.; TAMs
    DOI:  https://doi.org/10.1002/adhm.202300164
  26. Cell Death Dis. 2023 May 04. 14(5): 304
    CHRM4/AKT/MYCN upregulates interferon alpha-17 in the tumor microenvironment to promote neuroendocrine differentiation of prostate cancer.
    Yu-Ching Wen, Van Thi Ngoc Tram, Wei-Hao Chen, Chien-Hsiu Li, Hsiu-Lien Yeh, Phan Vu Thuy Dung, Kuo-Ching Jiang, Han-Ru Li, Jiaoti Huang, Michael Hsiao, Wei-Yu Chen, Yen-Nien Liu.
      Current treatment options for prostate cancer focus on targeting androgen receptor (AR) signaling. Inhibiting effects of AR may activate neuroendocrine differentiation and lineage plasticity pathways, thereby promoting the development of neuroendocrine prostate cancer (NEPC). Understanding the regulatory mechanisms of AR has important clinical implications for this most aggressive type of prostate cancer. Here, we demonstrated the tumor-suppressive role of the AR and found that activated AR could directly bind to the regulatory sequence of muscarinic acetylcholine receptor 4 (CHRM4) and downregulate its expression. CHRM4 was highly expressed in prostate cancer cells after androgen-deprivation therapy (ADT). CHRM4 overexpression may drive neuroendocrine differentiation of prostate cancer cells and is associated with immunosuppressive cytokine responses in the tumor microenvironment (TME) of prostate cancer. Mechanistically, CHRM4-driven AKT/MYCN signaling upregulated the interferon alpha 17 (IFNA17) cytokine in the prostate cancer TME after ADT. IFNA17 mediates a feedback mechanism in the TME by activating the CHRM4/AKT/MYCN signaling-driven immune checkpoint pathway and neuroendocrine differentiation of prostate cancer cells. We explored the therapeutic efficacy of targeting CHRM4 as a potential treatment for NEPC and evaluated IFNA17 secretion in the TME as a possible predictive prognostic biomarker for NEPC.
    DOI:  https://doi.org/10.1038/s41419-023-05836-7
  27. J Surg Res. 2023 May 02. pii: S0022-4804(23)00141-5. [Epub ahead of print]289 190-201
    CD69 on Tumor-Infiltrating Cells Correlates With Neuroblastoma Suppression by Simultaneous PD-1 and PD-L1 Blockade.
    Seiichiro Inoue, Yuta Takeuchi, Yutaka Horiuchi, Takashi Murakami, Akio Odaka.
       INTRODUCTION: Tumor-infiltrating cells play an important role in tumor immunology, and tumor-infiltrating lymphocytes (TILs) are critical in antitumor reaction related to immune checkpoint inhibition targeting programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1).
    METHODS: In nude mice, which are immune deficient because they lack T cells, and inbred A/J mice, which are syngeneic to neuroblastoma cells (Neuro-2a) and have normal T cell function, we investigated the importance of T lymphocytes in immune checkpoint inhibition in mouse neuroblastoma and analyzed the immune cells in the tumor microenvironment. Then, we subcutaneously injected mouse Neuro-2ainto nude mice and A/J mice, administered anti-PD-1 and anti-PD-L1 antibodies by intraperitoneal injection, and evaluated tumor growth. At 16 d after Neuro-2a cells injection, mice were euthanized, tumors and spleens were harvested, and immune cells were analyzed by flow cytometry.
    RESULTS: The antibodies suppressed tumor growth in A/J but not in nude mice. The co-administration of antibodies did not affect regulatory T cells (culster of differentiation [CD]4+CD25+FoxP3+ cells) or activated CD4+ lymphocytes (expressing CD69). No changes in activated CD8+ lymphocytes (expressing CD69) were observed in spleen tissue. However, increased infiltration of activated CD8+ TILs was seen in tumors weighing less than 300 mg, and the amount of activated CD8+ TILs was negatively correlated with tumor weight.
    CONCLUSIONS: Our study confirms that lymphocytes are essential for the antitumor immune reaction induced by blocking PD-1/PD-L1 and raises the possibility that promoting the infiltration of activated CD8+ TIL into tumors may be an effective treatment for neuroblastoma.
    Keywords:  CD69; Immune checkpoint inhibition; Neuroblastoma; programmed cell death ligand; programmed cell death protein 1
    DOI:  https://doi.org/10.1016/j.jss.2023.03.042
  28. Cell Biol Toxicol. 2023 May 03.
    Potential functions and therapeutic implications of glioma-resident mesenchymal stem cells.
    Qing Zhang, Jialin Wang, Junwen Zhang, Fusheng Liu.
      Mesenchymal stem cells (MSCs) are emerging crucial regulators in the tumor microenvironment (TME), which contributes to tumor progression and therapeutic resistance. MSCs are considered to be the stromal components of several tumors, their ultimate contribution to tumorigenesis and their potential to drive tumor stem cells, especially in the unique microenvironment of gliomas. Glioma-resident MSCs (GR-MSCs) are non-tumorigenic stromal cells. The phenotype of GR-MSCs is similar to that of prototype bone marrow-MSCs and GR-MSCs enhance the GSCs tumorigenicity via the IL-6/gp130/STAT3 pathway. The higher percentage of GR-MSCs in TME results in the poor prognosis of glioma patients and illuminate the tumor-promoting roles for GR-MSCs by secreting specific miRNA. Furthermore, the GR-MSC subpopulations associated with CD90 expression determine their different functions in glioma progression and CD90low MSCs generate therapeutic resistance by increasing IL-6-mediated FOXS1 expression. Therefore, it is urgent to develop novel therapeutic strategies targeting GR-MSCs for GBM patients. Despite that several functions of GR-MSCs have been confirmed, their immunologic landscapes and deeper mechanisms associated with the functions are not still expounded. In this review, we summarize the progress and potential function of GR-MSCs, as well as highlight their therapeutic implications based on GR-MSCs in GBM patients.
    Keywords:  Glioma; Glioma-resident mesenchymal stem cells; Mesenchymal stem cells; Tumor microenvironment; Tumor-promoting
    DOI:  https://doi.org/10.1007/s10565-023-09808-7
  29. Cell Commun Signal. 2023 May 04. 21(1): 96
    What is new in cancer-associated fibroblast biomarkers?
    Zehua Zhao, Tianming Li, Yuan Yuan, Yanmei Zhu.
      The tumor microenvironment is one of the important drivers of tumor development. Cancer-associated fibroblasts (CAFs) are a major component of the tumor stroma and actively participate in tumor development, invasion, metastasis, drug resistance, and other biological behaviors. CAFs are a highly heterogeneous group of cells, a reflection of the diversity of their origin, biomarkers, and functions. The diversity of CAF origin determines the complexity of CAF biomarkers, and CAF subpopulations expressing different biomarkers may play contrasting roles in tumor progression. In this review, we provide an overview of these emerging CAF biomarkers and the biological functions that they suggest, which may give a better understanding of the relationship between CAFs and tumor cells and be of great significance for breakthroughs in precision targeted therapy for tumors. Video Abstract.
    Keywords:  Biomarker; Cancer-associated fibroblasts; Heterogeneity; Targeted therapy
    DOI:  https://doi.org/10.1186/s12964-023-01125-0
  30. Cancer Res. 2023 May 02. 83(9): 1383-1385
    Understanding Long-Term Survival of Patients with Ovarian Cancer-The Tumor Microenvironment Comes to the Forefront.
    Lucy Kelliher, Ernst Lengyel.
      High-grade serous ovarian cancer (HGSOC) is the deadliest subtype of ovarian cancer, and most patients do not survive more than 5 years after diagnosis. Yet, for reasons that are often elusive, approximately 15% of women with advanced-stage HGSOC will survive longer than 10 years. An understanding of the biological basis of long-term survival with HGSOC may elucidate novel prognostic factors and targets for treatment. Past analyses of the clinicopathologic features of these women and genetic profiles of their tumors have not revealed a unifying explanation for their increased longevity. In this issue of Cancer Research, Ferri-Borgogno and colleagues investigate the tumor microenvironment (TME) in samples from both long- and short-term survivors using spatial transcriptomics and single-cell RNA sequencing. They found that, in metastatic tumors, various populations of cancer-associated fibroblasts (CAF) in the TME play different roles in supporting the malignant phenotype of ovarian cancer cells. Higher density of CAFs, particularly αSMA+VIM+PDGFRβ+ CAFs, was associated with lower tumor immune infiltration and short-term survival. There was also marked expression of periostin and CD36 in spatially resolved CAFs, as well as a prevalence of the APOE-LRP5 ligand-receptor pair at the tumor-stromal interface in tissue from short-term survivors. These findings suggest that, in short-term survivors, CAFs are able to more effectively promote tumorigenicity, stemness, and chemoresistance in the nearby tumor. See related article by Ferri-Borgogno et al., p. 1503.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0333
  31. Stem Cell Rev Rep. 2023 May 02.
    Cancer stem cells: an insight into the development of metastatic tumors and therapy resistance.
    Tahsin Nairuz, Zimam Mahmud, Rasel Khan Manik, Yearul Kabir.
      The term "cancer stem cells" (CSCs) refers to cancer cells that exhibit traits parallel to normal stem cells, namely the potential to give rise to every type of cell identified in a tumor microenvironment. It has been found that CSCs usually develops from other neoplastic cells or non-cancerous somatic cells by acquiring stemness and malignant characteristics through particular genetic modifications. A trivial number of CSCs, identified in solid and liquid cancer, can give rise to an entire tumor population with aggressive anticancer drug resistance, metastasis, and invasiveness. Besides, cancer stem cells manipulate their intrinsic and extrinsic features, regulate the metabolic pattern of the cell, adjust efflux-influx efficiency, modulate different signaling pathways, block apoptotic signals, and cause genetic and epigenetic alterations to retain their pluripotency and ability of self-renewal. Notably, to keep the cancer stem cells' ability to become malignant cells, mesenchymal stem cells, tumor-associated fibroblasts, immune cells, etc., interact with one another. Furthermore, CSCs are characterized by the expression of particular molecular markers that carry significant diagnostic and prognostic significance. Because of this, scientific research on CSCs is becoming increasingly imperative, intending to understand the traits and behavior of cancer stem cells and create more potent anticancer therapeutics to fight cancer at the CSC level. In this review, we aimed to elucidate the critical role of CSCs in the onset and spread of cancer and the characteristics of CSCs that promote severe resistance to targeted therapy.
    Keywords:  Cancer biomarkers; Cancer metastasis; Cancer stem cells; Therapy resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12015-023-10529-x
  32. Front Oncol. 2023 ;13 1112576
    Spatial transcriptomics reveals the heterogeneity and FGG+CRP+ inflammatory cancer-associated fibroblasts replace islets in pancreatic ductal adenocarcinoma.
    Zhangyong Ren, Bing Pan, Fangfei Wang, Shaocheng Lyu, Jialei Zhai, Xiumei Hu, Zhe Liu, Lixin Li, Ren Lang, Qiang He, Xin Zhao.
       Background: Understanding the spatial heterogeneity of the tumor microenvironment (TME) in pancreatic cancer (PC) remains challenging.
    Methods: In this study, we performed spatial transcriptomics (ST) to investigate the gene expression features across one normal pancreatic tissue, PC tissue, adjacent tumor tissue, and tumor stroma. We divided 18,075 spatial spots into 22 clusters with t-distributed stochastic neighbor embedding based on gene expression profiles. The biological functions and signaling pathways involved in each cluster were analyzed with gene set enrichment analysis.
    Results: The results revealed that KRT13+FABP5+ malignant cell subpopulation had keratinization characteristics in the tumor tissue. Fibroblasts from adjacent tumor tissue exhibited a tumor-inhibiting role such as "B-cell activation" and "positive regulation of leukocyte activation." The FGG+CRP+ inflammatory cancer-associated fibroblasts replaced the islets in tumor stroma. During PC progression, the damage to pancreatic structure and function was heavier in the pancreatic exocrine (AMYA2+PRSS1+) than in the endocrine (INS+GCG+).
    Conclusion: Our results revealed the spatial heterogeneity of dynamic changes and highlighted the significance of impaired exocrine function in PC.
    Keywords:  cancer-associated fibroblasts; heterogeneity; pancreatic ductal adenocarcinoma; spatial transcriptomics; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2023.1112576
  33. Cold Spring Harb Perspect Med. 2023 May 03. pii: a041320. [Epub ahead of print]
    Gene-Expression Profiling to Decipher Breast Cancer Inter- and Intratumor Heterogeneity.
    Alexander Swarbrick, Aranzazu Fernandez-Martinez, Charles M Perou.
      Breast cancer is heterogeneous and differs substantially across different tumors (intertumor heterogeneity) and even within an individual tumor (intratumor heterogeneity). Gene-expression profiling has considerably impacted our understanding of breast cancer biology. Four main "intrinsic subtypes" of breast cancer (i.e., luminal A, luminal B, HER2-enriched, and basal-like) have been consistently identified by gene expression, showing significant prognostic and predictive value in multiple clinical scenarios. Thanks to the molecular profiling of breast tumors, breast cancer is a paradigm of treatment personalization. Several standardized prognostic gene-expression assays are presently being used in the clinic to guide treatment decisions. Moreover, the development of single-cell-level resolution molecular profiling has allowed us to appreciate that breast cancer is also heterogeneous within a single tumor. There is an evident functional heterogeneity within the neoplastic and tumor microenvironment cells. Finally, emerging insights from these studies suggest a substantial cellular organization of neoplastic and tumor microenvironment cells, thus defining breast cancer ecosystems and highlighting the importance of spatial localizations.
    DOI:  https://doi.org/10.1101/cshperspect.a041320
  34. Front Pharmacol. 2023 ;14 1144330
    Synergistic effect of CD47 blockade in combination with cordycepin treatment against cancer.
    Chen Feng, Rongzhang Chen, Weiwei Fang, Xinran Gao, Hanjie Ying, Xiao Zheng, Lujun Chen, Jingting Jiang.
      Cordycepin is widely considered a direct tumor-suppressive agent. However, few studies have investigated as the effect of cordycepin therapy on the tumor microenvironment (TME). In our present study, we demonstrated that cordycepin could weaken the function of M1-like macrophages in the TME and also contribute to macrophage polarization toward the M2 phenotype. Herein, we established a combined therapeutic strategy combining cordycepin and an anti-CD47 antibody. By using single-cell RNA sequencing (scRNA-seq), we showed that the combination treatment could significantly enhance the effect of cordycepin, which would reactivate macrophages and reverse macrophage polarization. In addition, the combination treatment could regulate the proportion of CD8+ T cells to prolong the progression-free survival (PFS) of patients with digestive tract malignancies. Finally, flow cytometry validated the changes in the proportions of tumor-associated macrophages (TAMs) and tumor-infiltrating lymphocytes (TILs). Collectively, our findings suggested that the combination treatment of cordycepin and the anti-CD47 antibody could significantly enhance tumor suppression, increase the proportion of M1 macrophages, and decrease the proportion of M2 macrophages. In addition, the PFS in patients with digestive tract malignancies would be prolonged by regulating CD8 + T cells.
    Keywords:  anti-CD47; cordycepin; macrophage; scRNA-seq; tumor microenvironment
    DOI:  https://doi.org/10.3389/fphar.2023.1144330
  35. Front Oncol. 2023 ;13 1164266
    Metabonomic analysis of tumor microenvironments: a mini-review.
    Zeng Zeng, Cong-Xian Chen.
      Metabolomic analysis is a vital part of studying cancer progression. Metabonomic crosstalk, such as nutrient availability, physicochemical transformation, and intercellular interactions can affect tumor metabolism. Many original studies have demonstrated that metabolomics is important in some aspects of tumor metabolism. In this mini-review, we summarize the definition of metabolomics and how it can help change a tumor microenvironment, especially in pathways of three metabonomic tumors. Just as non-invasive biofluids have been identified as early biomarkers of tumor development, metabolomics can also predict differences in tumor drug response, drug resistance, and efficacy. Therefore, metabolomics is important for tumor metabolism and how it can affect oncology drugs in cancer therapy.
    Keywords:  drug resistance; metabolism; metabolomic; metabonomic; tumor
    DOI:  https://doi.org/10.3389/fonc.2023.1164266
  36. Front Immunol. 2023 ;14 1170603
    NETosis as an oncologic therapeutic target: a mini review.
    Sarah Jaboury, Kenny Wang, Kim Maree O'Sullivan, Joshua Daniel Ooi, Gwo Yaw Ho.
      Neutrophil Extracellular Traps (NETs) are a key form of pro-inflammatory cell death of neutrophils characterized by the extrusion of extracellular webs of DNA containing bactericidal killing enzymes. NETosis is heavily implicated as a key driver of host damage in autoimmune diseases where injurious release of proinflammatory enzymes damage surrounding tissue and releases 70 known autoantigens. Recent evidence shows that both neutrophils and NETosis have a role to play in carcinogenesis, both indirectly through triggering DNA damage through inflammation, and directly contributing to a pro-tumorigenic tumor microenvironment. In this mini-review, we summarize the current knowledge of the various mechanisms of interaction and influence between neutrophils, with particular attention to NETosis, and cancer cells. We will also highlight the potential avenues thus far explored where we can intercept these processes, with the aim of identifying promising prospective targets in cancer treatment to be explored in further studies.
    Keywords:  NETosis; cancer; innate immunity; neutrophil; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1170603
  37. bioRxiv. 2023 Apr 17. pii: 2023.04.15.536946. [Epub ahead of print]
    Molecular, metabolic and functional CD4 T cell paralysis impedes tumor control.
    Mengdi Guo, Diala Abd-Rabbo, Bruna Bertol, Madeleine Carew, Sabelo Lukhele, Laura M Snell, Wenxi Xu, Giselle M Boukhaled, Heidi Elsaesser, Marie Jo Halaby, Naoto Hirano, Tracy L McGaha, David G Brooks.
      CD4 T cells are important effectors of anti-tumor immunity, yet the regulation of CD4 tumor-specific T (T TS ) cells during cancer development is still unclear. We demonstrate that CD4 T TS cells are initially primed in the tumor draining lymph node and begin to divide following tumor initiation. Distinct from CD8 T TS cells and previously defined exhaustion programs, CD4 T TS cell proliferation is rapidly frozen in place and differentiation stunted by a functional interplay of T regulatory cells and both intrinsic and extrinsic CTLA4 signaling. Together these mechanisms paralyze CD4 T TS cell differentiation, redirecting metabolic and cytokine production circuits, and reducing CD4 T TS cell accumulation in the tumor. Paralysis is actively maintained throughout cancer progression and CD4 T TS cells rapidly resume proliferation and functional differentiation when both suppressive reactions are alleviated. Strikingly, Treg depletion alone reciprocally induced CD4 T TS cells to themselves become tumor-specific Tregs, whereas CTLA4 blockade alone failed to promote T helper differentiation. Overcoming their paralysis established long-term tumor control, demonstrating a novel immune evasion mechanism that specifically cripples CD4 T TS cells to favor tumor progression.
    DOI:  https://doi.org/10.1101/2023.04.15.536946
  38. Cancer Lett. 2023 May 03. pii: S0304-3835(23)00156-8. [Epub ahead of print] 216205
    Reprogramming of TAMs via the STAT3/CD47-SIRPα axis promotes acquired resistance to EGFR-TKIs in lung cancer.
    Jiaye Lu, Jingwei Li, Ziyou Lin, Huaxuan Li, Linlin Lou, Wen Ding, Shumin Ouyang, Wu Yonghui, Yuanzhen Wen, Xiaobing Chen, Peibin Yue, Yuanxiang Wang, Peiqing Liu, Jinjian Lu, Jian Zhang, Weineng Feng, Xiaolei Zhang.
      Cross-talk between the tumor microenvironment (TME) and cancer cells plays an important role in acquired drug resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). The role of tumor-associated macrophages (TAMs), the major component of the TME, in acquired resistance remains unclear. In this study, M2-like reprogramming of TAMs and reduced phagocytosis by macrophages were observed in gefitinib-resistant lung cancer cells and tumor xenografts. CD47 was upregulated in TKI-resistant lung cancer cells, and M2 macrophage polarization and cancer cell escape from macrophage phagocytosis were enhanced. Culture medium from TKI-resistant cells led to metabolic reprogramming of TAMs. STAT3 was associated with CD47 expression in TKI-resistant lung cancer cells. Genetic and pharmacological inhibition of STAT3 enhanced the phagocytic activity of TAMs and alleviated the acquired resistance to EGFR-TKIs via inhibiting the CD47-SIRPα signaling axis and M2 polarization in the co-culture system. Moreover, STAT3 transcriptionally regulated CD47 expression by binding to consensus DNA response elements in the intron of the CD47 gene. Furthermore, the combination of gefitinib with a STAT3 inhibitor and an anti-CD47 monoclonal antibody alleviated the acquired resistance to gefitinib in vitro and in vivo. Collectively, our study reveals the role of TAM reprogramming and the CD47-SIRPα axis in acquired EGFR-TKI resistance and provides a novel therapeutic strategy to overcome the acquired resistance to EGFR-TKIs in lung cancer.
    Keywords:  Acquired TKI resistance; CD47; Lung cancer; STAT3; TAMs
    DOI:  https://doi.org/10.1016/j.canlet.2023.216205
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