bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023–12–31
twenty-one papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Modifying CAR-T cells with anti-checkpoints in cancer immunotherapy: A focus on anti PD-1/PD-L1 antibodies.
  2. MiR-9 promotes G-MDSC recruitment and tumor proliferation by targeting SOCS3 in breast cancer.
  3. Repolarizing Tumor-Associated Macrophages and Inducing Immunogenic Cell Death: A Targeted Liposomal Strategy to Boost Cancer Immunotherapy.
  4. TTK inhibition activates STING signal and promotes anti-PD1 immunotherapy in breast cancer.
  5. Computational cell-cell interaction technologies drive mechanistic and biomarker discovery in the tumor microenvironment.
  6. FcγRIIB is an immune checkpoint limiting the activity of Treg-targeting antibodies in the tumor microenvironment.
  7. The current status and future of PD-L1 in liver cancer.
  8. Current progress of chimeric antigen receptor (CAR) T versus CAR NK cell for immunotherapy of solid tumors.
  9. Engineered 3D ex vivo models to recapitulate the complex stromal and immune interactions within the tumor microenvironment.
  10. Current Development Status of Cytokines for Cancer Immunotherapy.
  11. Alternative immune checkpoints in immunoregulatory profile of cancer stem cells.
  12. Peroxisome proliferator-activated receptors: A key link between lipid metabolism and cancer progression.
  13. The effects of anti-PD-L1 monoclonal antibody on the expression of angiogenesis and invasion-related genes.
  14. Metabolomics at the tumor microenvironment interface: Decoding cellular conversations.
  15. Editorial: Cancer cell adhesion, metastasis, and the immune response.
  16. Unique characteristics of the tumor immune microenvironment in young patients with metastatic colorectal cancer.
  17. Ultrasound-responsive spherical nucleic acid against c-Myc/PD-L1 to enhance anti-tumoral macrophages in triple-negative breast cancer progression.
  18. Mast Cell: A Mysterious Character in Skin Cancer.
  19. ADAM10 and Neprilysin level decreases in immune cells of mice bearing metastatic breast carcinoma: Possible role in cancer inflammatory response.
  20. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature.
  21. Reviewing the significance of dendritic cell vaccines in interrupting breast cancer development.
  1. Life Sci. 2023 Dec 26. pii: S0024-3205(23)01022-6. [Epub ahead of print] 122387
    Modifying CAR-T cells with anti-checkpoints in cancer immunotherapy: A focus on anti PD-1/PD-L1 antibodies.
    Sajad Najafi, Keywan Mortezaee.
      Chimeric antigen receptor-modified T (CAR-T) are genetically engineered cells to express tumor-specific antigens revolutionizing the treatment of hematologic malignancies. The hostile tumor microenvironment (TME) remains a challenge for CAR-T cell therapy in solid tumors. As a solution, combinational therapy with immune checkpoint inhibitors (ICIs) is shown to improve the safety and efficacy of CAR-T cell therapy. To avoid side effects related to the application of ICIs in combinational therapy, engineering CARs to express tumor-specific antigens may help improvement of clinical outcomes. Those CARs expressing single chain variable fragments (scFvs) or nanobodies against immune checkpoint stimulatory or inhibitory molecules, such as the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling axis are being extensively studied in various clinical trials. In this review, we discuss the significance of anti-PD-(L)1 scFv-expressing CAR-T cells in the treatment of human cancers, describing current challenges and potential strategies to overcome such predicaments in the area of cancer immunotherapy.
    Keywords:  Chimeric antigen receptor-modified T (CAR-T); Immune checkpoint inhibitor (ICI); Immunotherapy; Nanobody; Programmed death-1 (PD-1); Programmed death-ligand 1 (PD-L1); Single chain variable fragment (scFv)
    DOI:  https://doi.org/10.1016/j.lfs.2023.122387
  2. FASEB J. 2024 Jan;38(1): e23388
    MiR-9 promotes G-MDSC recruitment and tumor proliferation by targeting SOCS3 in breast cancer.
    Xinyue Gu, Fang Wei, Jinzhe Tong, Yichen Liu, Simiao Chen, Lufeng Zheng, Yingying Xing.
      Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of cells that differentiate from myeloid cells, proliferate in cancer and inflammatory reactions, and mainly exert immunosuppressive functions. Nonetheless, the precise mechanisms that dictate both the accumulation and function of MDSCs remain only partially elucidated. In the course of our investigation, we observed a positive correlation between the content of MDSCs especially G-MDSCs and miR-9 level in the tumor tissues derived from miR-9 knockout MMTV-PyMT mice and 4T1 tumor-bearing mice with miR-9 overexpression. Combined with RNA-seq analysis, we identified SOCS2 and SOCS3 as direct targets of miR-9. Additionally, our research unveiled the pivotal role of the CCL5/CCR5 axis in orchestrating the chemotactic recruitment of G-MDSCs within the tumor microenvironment, a process that is enhanced by miR-9. These findings provide fresh insights into the molecular mechanisms governing the accumulation of MDSCs within the framework of breast cancer development.
    Keywords:  MDSCs; SOCS; breast cancer; immune microenvironment; miR-9
    DOI:  https://doi.org/10.1096/fj.202301764RR
  3. Int J Pharm. 2023 Dec 21. pii: S0378-5173(23)01151-1. [Epub ahead of print] 123729
    Repolarizing Tumor-Associated Macrophages and Inducing Immunogenic Cell Death: A Targeted Liposomal Strategy to Boost Cancer Immunotherapy.
    Cong Li, Lihong Wang, Zhihang Li, Zehao Li, Kexin Zhang, Lianrui Cao, Zeyu Wang, Chao Shen, Lijiang Chen.
      Cancer immunotherapy has shown promise in treating various malignancies. However, the presence of an immunosuppressive tumor microenvironment (TME) triggered by M2 tumor-associated macrophages (TAMs) and the limited tumor cell antigenicity have hindered its broader application. To address these challenges, we developed DOX/R837@ManL, a liposome loaded with imiquimod (R837) and doxorubicin (DOX), modified with mannose-polyethylene glycol (Man-PEG). DOX/R837@ManL employed a mannose receptor (MRC1)-mediated targeting strategy, allowing it to accumulate selectively at M2 Tumor associated macrophages (TAMs) and tumor sites. R837, an immune adjuvant, promoted the conversion of immunosuppressive M2 TAMs into immunostimulatory M1 TAMs, and reshaped the immunosuppressive TME. Simultaneously, DOX release induced immunogenic cell death (ICD) in tumor cells and enhanced tumor cell antigenicity by promoting dendritic cells (DCs) maturation. Through targeted delivery, the synergistic action of R837 and DOX activated innate immunity and coordinated adaptive immunity, enhancing immunotherapy efficacy. In vivo experiments have demonstrated that DOX/R837@ManL effectively eliminated primary tumors and lung metastases, while also preventing tumor recurrence post-surgery. These findings highlighted the potential of DOX/R837@ManL as a promising strategy for cancer immunotherapy.
    Keywords:  Immunogenic cell death; Immunotherapy; Mannose-modified liposomes; Repolarization of M2 TAMs; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ijpharm.2023.123729
  4. Biochem Biophys Res Commun. 2023 Dec 18. pii: S0006-291X(23)01482-1. [Epub ahead of print]694 149388
    TTK inhibition activates STING signal and promotes anti-PD1 immunotherapy in breast cancer.
    Xiang Hu, Guangmei Li, Sisi Li, Qiwei Wang, Yuerong Wang, Peidong Zhang, Tianqiong Yang, Bo Yang, Luoting Yu, Zhihao Liu.
      Despite progress in the application of checkpoint immunotherapy against various tumors, attempts to utilize immune checkpoint blockade (ICB) agents in triple negative breast cancer (TNBC) have yielded limited clinical benefits. The low overall response rate of checkpoint immunotherapy in TNBC may be attributed to the immunosuppressive tumor microenvironment (TME). In this study, we investigated the role of mitogen-associated kinase TTK in reprogramming immune microenvironment in TNBC. Notably, TTK inhibition by BAY-1217389 induced DNA damage and the formation of micronuclei containing dsDNA in the cytosol, resulting in elicition of STING signal pathway and promoted antitumor immunity via the infiltration and activation of CD8+ T cells. Moreover, TTK inhibition also upregulated the expression of PD-L1, demonstrating a synergistic effect with anti-PD1 therapy in 4T1 tumor-bearing mice. Taken together, TTK inhibition facilitated anti-tumor immunity mediated by T cells and enhanced sensitivity to PD-1 blockade, providing a rationale for the combining TTK inhibitors with immune checkpoint blockade in clinical trials.
    Keywords:  Immunotherapy; PD-L1; STING; TTK; Tumor immune microenvironment
    DOI:  https://doi.org/10.1016/j.bbrc.2023.149388
  5. Curr Opin Biotechnol. 2023 Dec 23. pii: S0958-1669(23)00158-1. [Epub ahead of print]85 103048
    Computational cell-cell interaction technologies drive mechanistic and biomarker discovery in the tumor microenvironment.
    Avery Pong, Clarence K Mah, Gene W Yeo, Nathan E Lewis.
      Complex networks of cell-cell interactions (CCIs) within the tumor microenvironment (TME) play a crucial role in cancer persistence. These communication axes represent prime targets for therapeutic intervention, but our incomplete understanding of the cellular heterogeneity and interacting partners within the TME remains a stubborn barrier to complete drug responses. This review outlines recent advances in the study of CCIs that leverage single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) technologies that can clarify TME dynamics. We anticipate that these strategies will promote discovery of CCIs critical to the tumor-immune interface and will, by extension, expand the repertoire of druggable tumor biomarkers.
    DOI:  https://doi.org/10.1016/j.copbio.2023.103048
  6. Cancer Immunol Res. 2023 Dec 26.
    FcγRIIB is an immune checkpoint limiting the activity of Treg-targeting antibodies in the tumor microenvironment.
    David A Knorr, Lucas Blanchard, Rom S Leidner, Shawn M Jensen, Ryan Meng, Andrew Jones, Carmen Ballesteros-Merino, Richard B Bell, Maria Baez, Alessandra Marino, David Sprott, Carlo B Bifulco, Brian Piening, Rony Dahan, Juan C Osorio, Bernard A Fox, Jeffrey V Ravetch.
      Preclinical murine data indicate that Fc-dependent depletion of intratumoral regulatory T cells (Tregs) is a major mechanism of action of anti-CTLA-4. However, the two main antibodies administered to patients (Ipilimumab and Tremelimumab) do not recapitulate these effects. Here, we investigate the underlying mechanisms responsible for the limited Treg depletion observed with these therapies. Using an immunocompetent murine model humanized for CTLA-4 and Fcγ receptors (FcγRs), we show that Ipilimumab and Tremelimumab exhibit limited Treg depletion in tumors. Immune profiling of the tumor microenvironment (TME) in both humanized mice and humans revealed high expression of the inhibitory Fc receptor, FcγRIIB, which limits antibody-dependent cellular cytotoxicity/phagocytosis (ADCC/ADCP). Blocking FcγRIIB in humanized mice rescued the Treg-depleting capacity and antitumor activity of Ipilimumab. Furthermore, Fc engineering of antibodies targeting Treg-associated targets (CTLA-4 or CCR8) to minimize FcγRIIB binding significantly enhanced Treg depletion, resulting in increased antitumor activity across various tumor models. Our results define the inhibitory FcγRIIB as an immune checkpoint limiting antibody-mediated Treg depletion in the TME, and demonstrate Fc engineering as an effective strategy to overcome this limitation and improve the efficacy of Treg-targeting antibodies.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-0389
  7. Front Immunol. 2023 ;14 1323581
    The current status and future of PD-L1 in liver cancer.
    Liyuan Hao, Shenghao Li, Jiali Deng, Na Li, Fei Yu, Zhi Jiang, Junli Zhang, Xinli Shi, Xiaoyu Hu.
      The application of immunotherapy in tumor, especially immune checkpoint inhibitors (ICIs), has played an important role in the treatment of advanced unresectable liver cancer. However, the efficacy of ICIs varies greatly among different patients, which has aroused people's attention to the regulatory mechanism of programmed death ligand-1 (PD-L1) in the immune escape of liver cancer. PD-L1 is regulated by multiple levels and signaling pathways in hepatocellular carcinoma (HCC), including gene variation, epigenetic inheritance, transcriptional regulation, post-transcriptional regulation, and post-translational modification. More studies have also found that the high expression of PD-L1 may be the main factor affecting the immunotherapy of liver cancer. However, what is the difference of PD-L1 expressed by different types of cells in the microenvironment of HCC, and which type of cells expressed PD-L1 determines the effect of tumor immunotherapy remains unclear. Therefore, clarifying the regulatory mechanism of PD-L1 in liver cancer can provide more basis for liver cancer immunotherapy and combined immune treatment strategy. In addition to its well-known role in immune regulation, PD-L1 also plays a role in regulating cancer cell proliferation and promoting drug resistance of tumor cells, which will be reviewed in this paper. In addition, we also summarized the natural products and drugs that regulated the expression of PD-L1 in HCC.
    Keywords:  HCC; PD-L1; cancer; hepatocellular carcinoma; liver cancer
    DOI:  https://doi.org/10.3389/fimmu.2023.1323581
  8. Life Sci. 2023 Dec 23. pii: S0024-3205(23)01016-0. [Epub ahead of print]337 122381
    Current progress of chimeric antigen receptor (CAR) T versus CAR NK cell for immunotherapy of solid tumors.
    Abdolreza Esmaeilzadeh, Kaveh Hadiloo, Marjan Jabbari, Reza Elahi.
      Equipping cancer-fighting immune cells with chimeric antigen receptor (CAR) has gained immense attention for cancer treatment. CAR-engineered T cells (CAR T cells) are the first immune-engineered cells that have achieved brilliant results in anti-cancer therapy. Despite promising anti-cancer features, CAR T cells could also cause fatal side effects and have shown inadequate efficacy in some studies. This has led to the introduction of other candidates for CAR transduction, e.g., Natural killer cells (NK cells). Regarding the better safety profile and anti-cancer properties, CAR-armored NK cells (CAR NK cells) could be a beneficial and suitable alternative to CAR T cells. Since introducing these two cells as anti-cancer structures, several studies have investigated their efficacy and safety, and most of them have focused on hematological malignancies. Solid tumors have unique properties that make them more resistant and less curable cancers than hematological malignancies. In this review article, we conduct a comprehensive review of the structure and properties of CAR NK and CAR T cells, compare the recent experience of immunotherapy with CAR T and CAR NK cells in various solid cancers, and overview current challenges and future solutions to battle solid cancers using CARNK cells.
    Keywords:  CAR NK cell; CAR T cell; Chimeric antigen receptor; Clinical; Immunotherapy; Solid tumor
    DOI:  https://doi.org/10.1016/j.lfs.2023.122381
  9. Biomaterials. 2023 Dec 19. pii: S0142-9612(23)00436-2. [Epub ahead of print]305 122428
    Engineered 3D ex vivo models to recapitulate the complex stromal and immune interactions within the tumor microenvironment.
    Kalpana Ravi, Twinkle Jina Minette Manoharan, Kuei-Chun Wang, Barbara Pockaj, Mehdi Nikkhah.
      Cancer thrives in a complex environment where interactions between cellular and acellular components, surrounding the tumor, play a crucial role in disease development and progression. Despite significant progress in cancer research, the mechanism driving tumor growth and therapeutic outcomes remains elusive. Two-dimensional (2D) cell culture assays and in vivo animal models are commonly used in cancer research and therapeutic testing. However, these models suffer from numerous shortcomings including lack of key features of the tumor microenvironment (TME) & cellular composition, cost, and ethical clearance. To that end, there is an increased interest in incorporating and elucidating the influence of TME on cancer progression. Advancements in 3D-engineered ex vivo models, leveraging biomaterials and microengineering technologies, have provided an unprecedented ability to reconstruct native-like bioengineered cancer models to study the heterotypic interactions of TME with a spatiotemporal organization. These bioengineered cancer models have shown excellent capabilities to bridge the gap between oversimplified 2D systems and animal models. In this review article, we primarily provide an overview of the immune and stromal cellular components of the TME and then discuss the latest state-of-the-art 3D-engineered ex vivo platforms aiming to recapitulate the complex TME features. The engineered TME model, discussed herein, are categorized into three main sections according to the cellular interactions within TME: (i) Tumor-Stromal interactions, (ii) Tumor-Immune interactions, and (iii) Complex TME interactions. Finally, we will conclude the article with a perspective on how these models can be instrumental for cancer translational studies and therapeutic testing.
    Keywords:  3D printed; 3D-engineered models; Immune crosstalk; Microfluidics; Tumor immune microenvironment (TIME); Tumor microenvironment (TME); Tumor-on-chip
    DOI:  https://doi.org/10.1016/j.biomaterials.2023.122428
  10. Biomol Ther (Seoul). 2024 Jan 01. 32(1): 13-24
    Current Development Status of Cytokines for Cancer Immunotherapy.
    Kyoung Song.
      Cytokines influence the overall cancer immune cycle by triggering tumor antigen expression, antigen presenting, immune cell priming and activation, effector immune cell recruitment and infiltration to cancer, and cancer killing in the tumor microenvironment (TME). Therefore, cytokines have been considered potential anti-cancer immunotherapy, and cytokine-based anti-cancer therapies continue to be an active area of research and development in the field of cancer immunotherapy, with ongoing clinical trials exploring new strategies to improve efficacy and safety. In this review, we examine past and present clinical developments for major anticancer cytokines, including interleukins (IL-2, IL-15, IL-12, IL-21), interferons, TGF-beta, and GM-CSF. We identify the current status and changes in the technology platform being applied to cytokine-based immune anti-cancer therapeutics. Through this, we discuss the opportunities and challenges of cytokine-based immune anti-cancer treatments in the current immunotherapy market and suggest development directions to enhance the clinical use of cytokines as immuno-anticancer drugs in the future.
    Keywords:  Cancer; Clinical trials; Cytokine; Immunotherapy
    DOI:  https://doi.org/10.4062/biomolther.2023.196
  11. Heliyon. 2023 Dec;9(12): e23171
    Alternative immune checkpoints in immunoregulatory profile of cancer stem cells.
    Keywan Mortezaee, Jamal Majidpoor.
      Tumor-mediated bypass of immune checkpoint inhibitor (ICI) therapy with anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1, also called B7-H1 or CD274) or anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) is a challenge of current years in the area of cancer immunotherapy. Alternative immune checkpoints (AICs) are molecules beyond the common PD-1, PD-L1 or CTLA-4, and are upregulated in patients who show low/no ICI responses. These are members of B7 family including B7-H2 (ICOS-L), B7-H3 (CD276), B7-H4 (B7x), V-domain immunoglobulin suppressor of T cell activation (VISTA), B7-H6, HHLA2 (B7-H5/B7-H7) and catabolic enzymes like indoleamine 2,3-dioxygenase 1 (IDO1), and others that are also contributed to the regulation of tumor immune microenvironment (TIME). There is also strong evidence supporting the implication of AICs in regulation of cancer stemness and expanding the population of cancer stem cells (CSCs). CSCs display immunoregulatory capacity and represent multiple immune checkpoints either on their surface or inside. Besides, they are active promoters of resistance to the common ICIs. The aim of this review is to investigate interrelations between AICs with stemness and differentiation profile of cancer. The key message of this paper is that targeted checkpoints can be selected based on their impact on CSCs along with their effect on immune cells. Studies published so far mainly focused on immune cells as a target for anti-checkpoints. Ex vivo engineering of extracellular vesicles (EVs) equipped with CSC-targeted anti-checkpoint antibodies is without a doubt a key therapeutic target that can be under consideration in future research.
    Keywords:  Alternative immune checkpoint (AIC); Cancer stem cell (CSC); Immune checkpoint inhibitor (ICI); Resistance; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e23171
  12. Clin Nutr. 2023 Dec 09. pii: S0261-5614(23)00427-2. [Epub ahead of print]43(2): 332-345
    Peroxisome proliferator-activated receptors: A key link between lipid metabolism and cancer progression.
    Yunkuo Li, Yujie Pan, Xiaodong Zhao, Shouwang Wu, Faping Li, Yuxiong Wang, Bin Liu, Yanghe Zhang, Xin Gao, Yishu Wang, Honglan Zhou.
      Lipids represent the essential components of membranes, serve as fuels for high-energy processes, and play crucial roles in signaling and cellular function. One of the key hallmarks of cancer is the reprogramming of metabolic pathways, especially abnormal lipid metabolism. Alterations in lipid uptake, lipid desaturation, de novo lipogenesis, lipid droplets, and fatty acid oxidation in cancer cells all contribute to cell survival in a changing microenvironment by regulating feedforward oncogenic signals, key oncogenic functions, oxidative and other stresses, immune responses, or intercellular communication. Peroxisome proliferator-activated receptors (PPARs) are transcription factors activated by fatty acids and act as core lipid sensors involved in the regulation of lipid homeostasis and cell fate. In addition to regulating whole-body energy homeostasis in physiological states, PPARs play a key role in lipid metabolism in cancer, which is receiving increasing research attention, especially the fundamental molecular mechanisms and cancer therapies targeting PPARs. In this review, we discuss how cancer cells alter metabolic patterns and regulate lipid metabolism to promote their own survival and progression through PPARs. Finally, we discuss potential therapeutic strategies for targeting PPARs in cancer based on recent studies from the last five years.
    Keywords:  Anticancer therapy; Cancer; Metabolic reprogramming; PPAR
    DOI:  https://doi.org/10.1016/j.clnu.2023.12.005
  13. Turk J Biol. 2023 ;47(4): 262-275
    The effects of anti-PD-L1 monoclonal antibody on the expression of angiogenesis and invasion-related genes.
    Cansu Babahan, Samira Abdi Abgarmi, Fatma Gizem Sonugür, Müge Öçal, Hakan Akbulut.
       Background/aim: The role of PD-L1 in regulating the immunosuppressive tumor microenvironment via its binding on PD-1 receptors is extensively studied. The PD-1/PD-L1 axis is a significant way of cancer immune escape, and PD-L1 expression on tumor cells is suggested as a predictive marker for anti-PD-1/PD-L1 monoclonal antibodies (MoAbs). However, the tumor-intrinsic role of PD-L1 is not known well. Therefore, we aimed to investigate the effects of anti-PD-L1 antibodies on the expression of angiogenesis and metastasis-related genes in tumor cells.
    Materials and methods: The experiments were done with prostate cancer and melanoma cells with low PD-L1 expression (<5%) and prostate and breast cancer cells with high PD-L1 expression (>50%). The gene and protein expressions of VEGFA, E-cadherin, TGFβ1, EGFR, and bFGF in tumor cells were assayed at the 3 different doses of the anti-PD-L1 antibody.
    Results: We found that VEGFA, E-cadherin and TGFβ1 expressions increased in PD-L1 high cells but decreased in PD-L1 low cells after anti-PD-L1 treatment. EGFR expression levels were variable in PD-L1 high cells, while decreased in PD-L1 low cells upon treatment. Also, the anti-PD-L1 antibody was found to increase bFGF expression in the prostate cancer cell line with high PD-L1 expression.
    Conclusion: Our results suggest that the binding of PD-L1 on tumor cells by an anti-PD-L1 monoclonal antibody may affect tumor-intrinsic mechanisms. The activation of angiogenesis and metastasis-related pathways by anti-PD-L1 treatment in PD-L1 high tumors might be a tumor-promoting mechanism. The decrease of VEGFA, TGFβ1 and EGFR upon anti-PD-L1 treatment in PD-L1 low tumor cells provides a rationale for the use of those antibodies in PD-L1 low tumors.
    Keywords:  Anti-PD-L1; E-cadherin; PD-L1; VEGFA; immunotherapy; metastasis
    DOI:  https://doi.org/10.55730/1300-0152.2661
  14. Med Res Rev. 2023 Dec 26.
    Metabolomics at the tumor microenvironment interface: Decoding cellular conversations.
    Naomi Berrell, Habib Sadeghirad, Tony Blick, Charles Bidgood, Graham R Leggatt, Ken O'Byrne, Arutha Kulasinghe.
      Cancer heterogeneity remains a significant challenge for effective cancer treatments. Altered energetics is one of the hallmarks of cancer and influences tumor growth and drug resistance. Studies have shown that heterogeneity exists within the metabolic profile of tumors, and personalized-combination therapy with relevant metabolic interventions could improve patient response. Metabolomic studies are identifying novel biomarkers and therapeutic targets that have improved treatment response. The spatial location of elements in the tumor microenvironment are becoming increasingly important for understanding disease progression. The evolution of spatial metabolomics analysis now allows scientists to deeply understand how metabolite distribution contributes to cancer biology. Recently, these techniques have spatially resolved metabolite distribution to a subcellular level. It has been proposed that metabolite mapping could improve patient outcomes by improving precision medicine, enabling earlier diagnosis and intraoperatively identifying tumor margins. This review will discuss how altered metabolic pathways contribute to cancer progression and drug resistance and will explore the current capabilities of spatial metabolomics technologies and how these could be integrated into clinical practice to improve patient outcomes.
    Keywords:  cancer metabolism; glucose; immunotherapy; metabolic interventions; spatial biology
    DOI:  https://doi.org/10.1002/med.22010
  15. Front Cell Dev Biol. 2023 ;11 1347446
    Editorial: Cancer cell adhesion, metastasis, and the immune response.
    Claudia Tanja Mierke.
      
    Keywords:  ADAM8; cell mechanics; cervical carcinoma; epithelial-mesenchymal transition (EMT); immunotherapy; metastasis; splicing factors; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fcell.2023.1347446
  16. Front Immunol. 2023 ;14 1289402
    Unique characteristics of the tumor immune microenvironment in young patients with metastatic colorectal cancer.
    Brian D Griffith, Jenny Lazarus, Jake McGue, Santhoshi Krishnan, Michael I D'Angelica, Jinru Shia, Irina Dobrosotskaya, Jaiqi Shi, Jacob Edwards, Arvind Rao, Timothy L Frankel.
       Introduction: Metastatic colorectal cancer (mCRC) remains a common and highly morbid disease, with a recent increase in incidence in patients younger than 50 years. There is an acute need to better understand differences in tumor biology, molecular characteristics, and other age-related differences in the tumor microenvironment (TME).
    Methods: 111 patients undergoing curative-intent resection of colorectal liver metastases were stratified by age into those <50 years or >65 years old, and tumors were subjected to multiplex fluorescent immunohistochemistry (mfIHC) to characterize immune infiltration and cellular engagement.
    Results: There was no difference in infiltration or proportion of immune cells based upon age, but the younger cohort had a higher proportion of programmed death-ligand 1 (PD-L1)+ expressing antigen presenting cells (APCs) and demonstrated decreased intercellular distance and increased cellular engagement between tumor cells (TCs) and cytotoxic T lymphocytes (CTLs), and between TCs and APCs. These trends were independent of microsatellite instability in tumors.
    Discussion: Age-related differences in PD-L1 expression and cellular engagement in the tumor microenvironment of patients with mCRC, findings which were unrelated to microsatellite status, suggest a more active immune microenvironment in younger patients that may offer an opportunity for therapeutic intervention with immune based therapy.
    Keywords:  colorectal cancer; immunotherapy; multiplex immunohistochemistry (IHC); spatial relation analysis; tumor immunology
    DOI:  https://doi.org/10.3389/fimmu.2023.1289402
  17. Sci China Life Sci. 2023 Nov 30.
    Ultrasound-responsive spherical nucleic acid against c-Myc/PD-L1 to enhance anti-tumoral macrophages in triple-negative breast cancer progression.
    Runtian Wang, Gaigai Li, Fangyan Gao, Feng Xu, Xintong Li, Jian Zhang, Jinbo Li, Xiaoxiang Guan.
      Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype because of its aggressive behavior and limited therapeutic targets. c-Myc is hyperactivated in the majority of TNBC tissues, however, it has been considered an "undruggable" target due to its disordered structure. Herein, we developed an ultrasound-responsive spherical nucleic acid (SNA) against c-Myc and PD-L1 in TNBC. It is a self-assembled and carrier-free system composed of a hydrophilic small-interfering RNA (siRNA) shell and a hydrophobic core made of a peptide nucleic acid (PNA)-based antisense oligonucleotide (ASO) and a sonosensitizer. We accomplished significant enrichment in the tumor by enhanced permeability and retention (EPR) effect, the controllable release of effective elements by ultrasound activation, and the combination of targeted therapy, immunotherapy and physiotherapy. Our study demonstrated significant anti-tumoral effects in vitro and in vivo. Mass cytometry showed an invigorated tumor microenvironment (TME) characterized by a significant alteration in the composition of tumor-associated macrophages (TAM) and decreased proportion of PD-1-positive (PD-1+) T effector cells after appropriate treatment of the ultrasound-responsive SNA (USNA). Further experiments verified that tumor-conditioned macrophages residing in the TME were transformed into the anti-tumoral population. Our finding offers a novel therapeutic strategy against the "undruggable" c-Myc, develops a new targeted therapy for c-Myc/PD-L1 and provides a treatment option for the TNBC.
    Keywords:  c-Myc; self-assembly; spherical nucleic acid; triple-negative breast cancer
    DOI:  https://doi.org/10.1007/s11427-023-2433-y
  18. In Vivo. 2024 Jan-Feb;38(1):38(1): 58-68
    Mast Cell: A Mysterious Character in Skin Cancer.
    Silvia Alda, Raluca Amalia Ceausu, Pusa Nela Gaje, Marius Raica, Raluca Mioara Cosoroaba.
      Cutaneous malignancies represent a real concern and burden for the healthcare system, not only due to their increased frequency, but also due to the significant number of deaths attributed to these types of cancer. The genesis of tumors, their progression and metastasis are highly complex and researched subjects; apparently, mast cells (MCs) constitute an important piece in the complicated jigsaw puzzle of cancer. This article reviews the current knowledge of the roles MCs might play in the development of cutaneous malignancies. Besides their well-known and studied role in allergic reactions, MCs are linked to multiple and various disorders, including cancer. MCs exhibit incredible heterogeneity, being able to secrete numerous mediators that influence the tumor microenvironment and tumor cells. They are involved in many physiological and pathological processes, such as inflammation and angiogenesis. In this context, it is paramount to explore the advancements made so far in elucidating the roles that MCs have in skin cancer because they might provide valuable therapeutic targets in the future. Controversial and conflicting results were obtained across the studies examined.
    Keywords:  Mast cell; mediators; review; skin cancer; tumor microenvironment
    DOI:  https://doi.org/10.21873/invivo.13410
  19. Int Immunopharmacol. 2023 Dec 22. pii: S1567-5769(23)01711-3. [Epub ahead of print]127 111384
    ADAM10 and Neprilysin level decreases in immune cells of mice bearing metastatic breast carcinoma: Possible role in cancer inflammatory response.
    Nuray Erin, Özlem Akdeniz.
       OBJECTIVE AND DESIGN: ADAM10 and Neprilysin, proteases, play critical role in inflammatory disease, however their role in cancer immune response is not clear. We here evaluated changes in immune response using an experimental model for breast cancer.
    MATERIAL AND METHOD: Highly metastatic breast cancer cells (4T1-derived) were injected orthotopically (mammary-pad of Balb-c mice) to induce tumors. Changes in enzyme level and activity as well as alterations in inflammatory cytokine release in the presence or absence of ADAM10 and NEP activity was determined using specific inhibitors and recombinant proteins. Cytokine response was evaluated using mix leucocyte cultures obtained from control and tumor-bearing mice. ANOVA with Dunnett's posttest was used for statistical analysis.
    RESULTS: ADAM10 and NEP expression was decreased markedly in lymph nodes and spleens of tumor-bearing mice. ADAM10 activity was reduced together with apparent alterations of ADAM10 processing. ADAM10 and NEP activity decreased TNF-α, IL-6 and IFN-ɣ secretion. Suppression of these inflammatory cytokines were more prominent in cultures obtained from control mice demonstrating counteracting factors that are exist in tumor-bearing mice.
    CONCLUSION: Loss of ADAM10 and NEP activity in immune cells during breast cancer metastasis might be one of the main factors involved in induction of chronic inflammation by tumors.
    Keywords:  4T1; ADAM10; Breast cancer; CD10; Cytokine; Metastasis
    DOI:  https://doi.org/10.1016/j.intimp.2023.111384
  20. Open Med (Wars). 2023 ;18(1): 20230866
    VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature.
    Ran Ren, Xin Chang, Cong Chen, Hao Yu, Lu Han.
      V-domain Ig suppressor of T cell activation (VISTA), encoded by the human VSIR gene, is a B7 family checkpoint homologous to the programmed death-Ligand 1 sequence. In gynecologic malignancies, VISTA is abnormally expressed and regulates the tumor immune microenvironment, causing a high upregulation of VISTA expression in T-cells and myeloid cells in the tumor microenvironment and promoting tumor proliferation, progression, and immune tolerance. Here, we review the research progress of VISTA in ovarian, cervical, and endometrial cancers through its structure and immunomodulatory mechanism. The comprehensive study of VISTA is expected to improve the current problem of poor immunotherapeutic effects and provide new ideas for immune therapy in patients with gynecologic tumors.
    Keywords:  VISTA; immunotherapy; malignant tumors; tumor microenvironment
    DOI:  https://doi.org/10.1515/med-2023-0866
  21. Mol Aspects Med. 2023 Dec 26. pii: S0098-2997(23)00079-1. [Epub ahead of print]95 101239
    Reviewing the significance of dendritic cell vaccines in interrupting breast cancer development.
    Namrata Gautam, Ganesan Ramamoorthi, Nicholas Champion, Hyo S Han, Brian J Czerniecki.
      Breast cancer is a heterogeneous disease and is the most prevalent cancer in women. According to the U.S breast cancer statistics, about 1 in every 8 women develop an invasive form of breast cancer during their lifetime. Immunotherapy has been a significant advancement in the treatment of cancer with multiple studies reporting favourable patient outcomes by modulating the immune response to cancer cells. Here, we review the significance of dendritic cell vaccines in treating breast cancer patients. We discuss the involvement of dendritic cells and oncodrivers in breast tumorigenesis, highlighting the rationale for targeting oncodrivers and neoantigens using dendritic cell vaccine therapy. We review different dendritic cell subsets and maturation states previously used to develop vaccines and suggest the use of DC vaccines for breast cancer prevention. Further, we highlight that the intratumoral delivery of type 1 dendritic cell vaccines in breast cancer patients activates tumor antigen-specific CD4+ T helper cell type 1 (Th1) cells, promoting an anti-tumorigenic immune response while concurrently blocking pro-tumorigenic responses. In summary, this review provides an overview of the current state of dendritic cell vaccines in breast cancer highlighting the challenges and considerations necessary for an efficient dendritic cell vaccine design in interrupting breast cancer development.
    Keywords:  Anti-tumor response; CD4(+) Th1 immune response; Dendritic cells; Intratumoral delivery; Oncodrivers
    DOI:  https://doi.org/10.1016/j.mam.2023.101239
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