bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023‒04‒09
29 papers selected by
Peio Azcoaga
Biodonostia HRI
  1. Targeting myeloid-derived suppressor cells in tumor immunotherapy: Current, future and beyond.
  2. The current understanding of the immune landscape relative to radiotherapy across tumor types.
  3. MDSCs: The Key Players in the Formation of Pre-Metastatic Niche.
  4. Lipid metabolism reprogramming in tumor-associated macrophages and implications for therapy.
  5. Tregs and Platelets Play Synergistic Roles in Tumor Immune Escape and Inflammatory Diseases.
  6. CAFs orchestrates tumor immune microenvironment-A new target in cancer therapy?
  7. Editorial: Molecular targeting of the tumor microenvironment for therapeutics in cancer metastasis.
  8. A key driver to promote HCC: Cellular crosstalk in tumor microenvironment.
  9. Targeting the NF-κB pathway enhances responsiveness of mammary tumors to JAK inhibitors.
  10. Extracellular vesicles: A dive into their role in the tumor microenvironment and cancer progression.
  11. Targeting tumor microenvironment using tumor-infiltrating lymphocytes as therapeutics against tumorigenesis.
  12. Macrophages facilitate tumor cell PD-L1 expression via an IL-1β-centered loop to attenuate immune checkpoint blockade.
  13. Overcoming anti-PD-1/PD-L1 immune checkpoint blockade resistance: the role of macrophage, neutrophils and mast cells in the tumor microenvironment.
  14. Integrative single-cell sequencing analysis distinguishes survival-associated cells from the breast cancer microenvironment.
  15. Mechano-modulation of T cells for cancer immunotherapy.
  16. Tumor microenvironment signaling and therapeutics in cancer progression.
  17. Expressing IL-15/IL-18 and CXCR2 improve infiltration and survival of EGFRvIII-targeting CAR-T cells in breast cancer.
  18. Current progress in chimeric antigen receptor-modified T cells for the treatment of metastatic breast cancer.
  19. The current landscape of CAR T-cell therapy for solid tumors: Mechanisms, research progress, challenges, and counterstrategies.
  20. Metabolic reprogramming of the ovarian cancer microenvironment in the development of antiangiogenic resistance.
  21. Ferroptosis: Promising approach for cancer and cancer immunotherapy.
  22. NAD+ biosynthesis metabolism predicts prognosis and indicates immune microenvironment for breast cancer.
  23. Interplay between stress and cancer-A focus on inflammation.
  24. Does burning fat make tumor immune hot? Discovery of CD47 overexpression by radiation induced fatty acid oxidation.
  25. Beyond checkpoint inhibition: PD-1 cis-targeting of an IL-2Rβγ-biased interleukin-2 variant as a novel approach to build on checkpoint inhibition.
  26. Immunotherapy for HER-2 positive breast cancer.
  27. Pan-cancer analysis identifies PD-L2 as a tumor promotor in the tumor microenvironment.
  28. The impact of hypoxia on tumor-mediated bypassing anti-PD-(L)1 therapy.
  29. IL-18 and VEGF-A trigger type 2 innate lymphoid cell accumulation and pro-tumoral function in chronic myeloid leukemia.
  1. Front Immunol. 2023 ;14 1157537
    Targeting myeloid-derived suppressor cells in tumor immunotherapy: Current, future and beyond.
    Yang Zhao, Junfeng Du, Xiaofei Shen.
      Myeloid-derived suppressor cells (MDSCs) are one of the major negative regulators in tumor microenvironment (TME) due to their potent immunosuppressive capacity. MDSCs are the products of myeloid progenitor abnormal differentiation in bone marrow, which inhibits the immune response mediated by T cells, natural killer cells and dendritic cells; promotes the generation of regulatory T cells and tumor-associated macrophages; drives the immune escape; and finally leads to tumor progression and metastasis. In this review, we highlight key features of MDSCs biology in TME that are being explored as potential targets for tumor immunotherapy. We discuss the therapies and approaches that aim to reprogram TME from immunosuppressive to immunostimulatory circumstance, which prevents MDSC immunosuppression activity; promotes MDSC differentiation; and impacts MDSC recruitment and abundance in tumor site. We also summarize current advances in the identification of rational combinatorial strategies to improve clinical efficacy and outcomes of cancer patients, via deeply understanding and pursuing the mechanisms and characterization of MDSCs generation and suppression in TME.
    Keywords:  cell therapy; combinatorial strategies; myeloid-derived suppressor cells; tumor immune microenvironment; tumor immunotherapy
    DOI:  https://doi.org/10.3389/fimmu.2023.1157537
  2. Front Immunol. 2023 ;14 1148692
    The current understanding of the immune landscape relative to radiotherapy across tumor types.
    Chrysanthi Iliadi, Laurine Verset, Christelle Bouchart, Philippe Martinive, Dirk Van Gestel, Mohammad Krayem.
      Radiotherapy is part of the standard of care treatment for a great majority of cancer patients. As a result of radiation, both tumor cells and the environment around them are affected directly by radiation, which mainly primes but also might limit the immune response. Multiple immune factors play a role in cancer progression and response to radiotherapy, including the immune tumor microenvironment and systemic immunity referred to as the immune landscape. A heterogeneous tumor microenvironment and the varying patient characteristics complicate the dynamic relationship between radiotherapy and this immune landscape. In this review, we will present the current overview of the immunological landscape in relation to radiotherapy in order to provide insight and encourage research to further improve cancer treatment. An investigation into the impact of radiation therapy on the immune landscape showed in several cancers a common pattern of immunological responses after radiation. Radiation leads to an upsurge in infiltrating T lymphocytes and the expression of programmed death ligand 1 (PD-L1) which can hint at a benefit for the patient when combined with immunotherapy. In spite of this, lymphopenia in the tumor microenvironment of 'cold' tumors or caused by radiation is considered to be an important obstacle to the patient's survival. In several cancers, a rise in the immunosuppressive populations is seen after radiation, mainly pro-tumoral M2 macrophages and myeloid-derived suppressor cells (MDSCs). As a final point, we will highlight how the radiation parameters themselves can influence the immune system and, therefore, be exploited to the advantage of the patient.
    Keywords:  biomarker; cancer; immune cells; immune landscape; immune tumor microenvironment; radiotherapy; systemic immune response
    DOI:  https://doi.org/10.3389/fimmu.2023.1148692
  3. Front Biosci (Landmark Ed). 2023 03 20. 28(3): 58
    MDSCs: The Key Players in the Formation of Pre-Metastatic Niche.
    Weigang Cui, Ziyi Wang, Jie Lv, Yan Qin, Huifang Shi.
      The distal metastasis of tumor cells is viewed as a series of concurrent processes rather than a linear cascade of events. Accompanied with the progression of the primary tumor, a favorable microenvironment, refered as pre-metastatic niche, has been created in pre-metastatic organs and sites by primary tumors for subsequent metastases. The proposal of "pre-metastatic niche" theory brings fresh insight into our understanding of cancer metastasis. Myeloid-derived suppressor cells (MDSCs) are indispensable for the formation of pre-metastatic niche, which empower the niche to favor tumor cell colonization and promote metastasis. In this review, we aim to provide a comprehensive understanding of the regulation of pre-metastatic niche formation by MDSCs and to conceptualize the framework for understanding the related factors involved in cancer metastasis.
    Keywords:  MDSCs; function; pre-metastatic niche; recruitment
    DOI:  https://doi.org/10.31083/j.fbl2803058
  4. Lipids Health Dis. 2023 Mar 31. 22(1): 45
    Lipid metabolism reprogramming in tumor-associated macrophages and implications for therapy.
    Xuehan Qiao, Zhangmin Hu, Fen Xiong, Yufei Yang, Chen Peng, Deqiang Wang, Xiaoqin Li.
      The tumormicroenvironment (TME) plays a key role in tumor progression. Tumor-associated macrophages (TAMs), which are natural immune cells abundantin the TME, are mainly divided into the anti-tumor M1 subtype and pro-tumor M2 subtype. Due to the high plasticity of TAMs, the conversion of the M1 to M2 phenotype in hypoxic and hypoglycemic TME promotes cancer progression, which is closely related to lipid metabolism. Key factors of lipid metabolism in TAMs, including peroxisome proliferator-activated receptor and lipoxygenase, promote the formation of a tumor immunosuppressive microenvironment and facilitate immune escape. In addition, tumor cells promote lipid accumulation in TAMs, causing TAMs to polarize to the M2 phenotype. Moreover, other factors of lipid metabolism, such as abhydrolase domain containing 5 and fatty acid binding protein, have both promoting and inhibiting effects on tumor cells. Therefore, further research on lipid metabolism in tumors is still required. In addition, statins, as core drugs regulating cholesterol metabolism, can inhibit lipid rafts and adhesion of tumor cells, which can sensitize them to chemotherapeutic drugs. Clinical studies on simvastatin and lovastatin in a variety of tumors are underway. This article provides a comprehensive review of the role of lipid metabolism in TAMs in tumor progression, and provides new ideas for targeting lipid metabolism in tumor therapy.
    Keywords:  Chemotherapy resistance; Immunotherapy; Lipid metabolism; Tumor-associated macrophages
    DOI:  https://doi.org/10.1186/s12944-023-01807-1
  5. Crit Rev Immunol. 2022 ;42(2): 59-69
    Tregs and Platelets Play Synergistic Roles in Tumor Immune Escape and Inflammatory Diseases.
    Huihui Gao, Ying Zhou, Xue Chen.
      Regulatory T cells (Tregs), a fraction of CD4+ T cells with immunosuppressive characteristics, are strongly linked to a number of inflammatory and autoimmune disorders. Furthermore, it also contributes to the development of tumors. Tregs infiltrate into the tumor microenvironment (TME), dampen the anti-tumor immune reaction, and facilitate tumoral immune escape. Besides the well-known hemostatic roles, mounting evidence indicates that platelets may also function as immune cells and engage in cancer immune escape. In addition, substantial evidence shows that platelets or platelet-derived mediators can regulate the proliferation, differentiation, and functions of many immune cells. Platelets also play important roles in promoting tumor cell proliferation and helping tumor cells evade immune surveillance. Here we summarize the regulatory effects of platelets in Treg proliferation, differentiation and functions and highlight the potential synergistic roles of platelets and Tregs in tumor cell immune escape.
    DOI:  https://doi.org/10.1615/CritRevImmunol.2023047234
  6. Front Pharmacol. 2023 ;14 1113378
    CAFs orchestrates tumor immune microenvironment-A new target in cancer therapy?
    Chunxue Zhang, Yuxiang Fei, Hui Wang, Sheng Hu, Chao Liu, Rong Hu, Qianming Du.
      Cancer immunotherapy has opened a new landscape in cancer treatment, however, the poor specificity and resistance of most targeted therapeutics have limited their therapeutic efficacy. In recent years, the role of CAFs in immune regulation has been increasingly noted as more evidence has been uncovered regarding the link between cancer-associated fibroblasts (CAFs) and the evolutionary process of tumor progression. CAFs interact with immune cells to shape the tumor immune microenvironment (TIME) that favors malignant tumor progression, a crosstalk process that leads to the failure of cancer immunotherapies. In this review, we outline recent advances in the immunosuppressive function of CAFs, highlight the mechanisms of CAFs-immune cell interactions, and discuss current CAF-targeted therapeutic strategies for future study.
    Keywords:  CAF-targeted therapy; cancer; cancer-associated fibroblasts; immune cells; tumor microenvironment
    DOI:  https://doi.org/10.3389/fphar.2023.1113378
  7. Front Mol Biosci. 2023 ;10 1178488
    Editorial: Molecular targeting of the tumor microenvironment for therapeutics in cancer metastasis.
    Subramanyam Dasari, Prabhakar Pitta Venkata, Uday P Pratap, Ram Mohan Ram Kumar.
      
    Keywords:  extracellular matrix (ECM); immune checkpoints; legumain (LGMN); metastasis; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fmolb.2023.1178488
  8. Front Oncol. 2023 ;13 1135122
    A key driver to promote HCC: Cellular crosstalk in tumor microenvironment.
    Pengyue Liu, Lingyu Kong, Ying Liu, Gang Li, Jianjia Xie, Xin Lu.
      Liver cancer is the third greatest cause of cancer-related mortality, which of the major pathological type is hepatocellular carcinoma (HCC) accounting for more than 90%. HCC is characterized by high mortality and is predisposed to metastasis and relapse, leading to a low five-year survival rate and poor clinical prognosis. Numerous crosstalk among tumor parenchymal cells, anti-tumor cells, stroma cells, and immunosuppressive cells contributes to the immunosuppressive tumor microenvironment (TME), in which the function and frequency of anti-tumor cells are reduced with that of associated pro-tumor cells increasing, accordingly resulting in tumor malignant progression. Indeed, sorting out and understanding the signaling pathways and molecular mechanisms of cellular crosstalk in TME is crucial to discover more key targets and specific biomarkers, so that develop more efficient methods for early diagnosis and individualized treatment of liver cancer. This piece of writing offers insight into the recent advances in HCC-TME and reviews various mechanisms that promote HCC malignant progression from the perspective of mutual crosstalk among different types of cells in TME, aiming to assist in identifying the possible research directions and methods in the future for discovering new targets that could prevent HCC malignant progression.
    Keywords:  cellular crosstalk; hepatocellular carcinoma (HCC); tumor immunosuppression; tumor malignant progression; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fonc.2023.1135122
  9. Sci Rep. 2023 Apr 01. 13(1): 5349
    Targeting the NF-κB pathway enhances responsiveness of mammary tumors to JAK inhibitors.
    Aditi S Bapat, Christine H O'Connor, Kathryn L Schwertfeger.
      Interactions between tumor cells and the tumor microenvironment are critical for tumor growth, progression, and response to therapy. Effective targeting of oncogenic signaling pathways in tumors requires an understanding of how these therapies impact both tumor cells and cells within the tumor microenvironment. One such pathway is the janus kinase (JAK)/signal transducer and activator or transcription (STAT) pathway, which is activated in both breast cancer cells and in tumor associated macrophages. This study demonstrates that exposure of macrophages to JAK inhibitors leads to activation of NF-κB signaling, which results in increased expression of genes known to be associated with therapeutic resistance. Furthermore, inhibition of the NF-κB pathway improves the ability of ruxolitinib to reduce mammary tumor growth in vivo. Thus, the impact of the tumor microenvironment is an important consideration in studying breast cancer and understanding such mechanisms of resistance is critical to development of effective targeted therapies.
    DOI:  https://doi.org/10.1038/s41598-023-32321-0
  10. Front Cell Dev Biol. 2023 ;11 1154576
    Extracellular vesicles: A dive into their role in the tumor microenvironment and cancer progression.
    Kassandra Lopez, Seigmund Wai Tsuen Lai, Edwin De Jesus Lopez Gonzalez, Raúl G Dávila, Sarah C Shuck.
      Extracellular vesicles (EVs) encompass a diverse set of membrane-derived particles released from cells and are found in numerous biological matrices and the extracellular space. Specific classes of EVs include apoptotic bodies, exosomes, and microvesicles, which vary in their size, origin, membrane protein expression, and interior cargo. EVs provide a mechanism for shuttling cargo between cells, which can influence cell physiology by transporting proteins, DNA, and RNA. EVs are an abundant component of the tumor microenvironment (TME) and are proposed to drive tumor growth and progression by communicating between fibroblasts, macrophages, and tumor cells in the TME. The cargo, source, and type of EV influences the pro- or anti-tumoral role of these molecules. Therefore, robust EV isolation and characterization techniques are required to ensure accurate elucidation of their association with disease. Here, we summarize different EV subclasses, methods for EV isolation and characterization, and a selection of current clinical trials studying EVs. We also review key studies exploring the role and impact of EVs in the TME, including how EVs mediate intercellular communication, drive cancer progression, and remodel the TME.
    Keywords:  cancer; cancer-derived extracellular vesicles; cargo transport; extracellular matrix; extracellular signaling; extracellular vesicles; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2023.1154576
  11. Immunol Res. 2023 Apr 01.
    Targeting tumor microenvironment using tumor-infiltrating lymphocytes as therapeutics against tumorigenesis.
    Hina Qayoom, Shazia Sofi, Manzoor A Mir.
      The immune system plays a vital role in suppressing tumor cell progression. The tumor microenvironment augmented with significant levels of tumor-infiltrating lymphocytes has been widely investigated and it is suggested that tumor-infiltrating lymphocytes have shown a significant role in the prognosis of cancer patients. Compared to ordinary non-infiltrating lymphocytes, tumor-infiltrating lymphocytes (TILs) are a significant population of lymphocytes that infiltrate tumor tissue and have a higher level of specific immunological reactivity against tumor cells. They serve as an effective immunological defense against various malignancies. TILs are a diverse group of immune cells that are divided into immune subsets based on the pathological and physiological impact they have on the immune system. TILs mainly consist of B-cells, T-cells, or natural killer cells with diverse phenotypic and functional properties. TILs are known to be superior to other immune cells in that they can recognize a wide range of heterogeneous tumor antigens by producing many clones of T cell receptors (TCRs), outperforming treatments like TCR-T cell and CAR-T therapy. With the introduction of genetic engineering technologies, tumor-infiltrating lymphocytes (TILs) have become a ground-breaking therapeutic option for malignancies, but because of the hindrances opposed by the immune microenvironment and the mutation of antigens, the development of TILs as therapeutic has been hindered. By giving some insight into the many variables, such as the various barriers inhibiting its usage as a potential therapeutic agent, we have examined various aspects of TILs in this work.
    Keywords:  Genetic engineering; Immune-surveillance; Next-generation TILs; TIL therapy; Tumor-infiltrating lymphocytes; Tumor-microenvironment
    DOI:  https://doi.org/10.1007/s12026-023-09376-2
  12. MedComm (2020). 2023 Apr;4(2): e242
    Macrophages facilitate tumor cell PD-L1 expression via an IL-1β-centered loop to attenuate immune checkpoint blockade.
    Cheng Xu, Yu Xia, Bai-Wei Zhang, Emmanuel Kwateng Drokow, Hua-Yi Li, Sen Xu, Zhen Wang, Si-Yuan Wang, Ping Jin, Tian Fang, Xiao-Ming Xiong, Pu Huang, Ning Jin, Jia-Hong Tan, Qing Zhong, Yu-Xin Chen, Qi Zhang, Yong Fang, Fei Ye, Qing-Lei Gao.
      Tumor-associated macrophages (TAMs) play critical roles in reprogramming other immune cells and orchestrating antitumor immunity. However, the interplay between TAMs and tumor cells responsible for enhancing immune evasion remains insufficiently understood. Here, we revealed that interleukin (IL)-1β was among the most abundant cytokines within the in vitro tumor-macrophage coculture system, and enhanced IL-1β expression was associated with impaired cytotoxicity of CD8+ T cells in human ovarian cancer, indicating the possibility that IL-1β mediated immunosuppression during tumor-TAMs crosstalk. Mechanistically, we demonstrated that IL-1β significantly boosted programmed death-ligand 1 (PD-L1) expression in tumor cells via the activation of the nuclear factor-κb signaling cascade. Specifically, IL-1β released from TAMs was triggered by lactate, the anaerobic metabolite of tumor cells, in an inflammasome activation-dependent manner. IL-1β sustained and intensified immunosuppression by promoting C-C motif chemokine ligand 2 secretion in tumor cells to fuel TAMs recruitment. Importantly, IL-1β neutralizing antibody significantly curbed tumor growth and displayed synergistic antitumor efficacies with anti-PD-L1 antibody in tumor-bearing mouse models. Together, this study presents an IL-1β-centered immunosuppressive loop between TAMs and tumor cells, highlighting IL-1β as a candidate therapeutic target to reverse immunosuppression and potentiate immune checkpoint blockade.
    Keywords:  immune checkpoint blockade; interleukin‐1β; programmed death‐ligand 1; tumor‐associated macrophages; tumor‐immune microenvironment
    DOI:  https://doi.org/10.1002/mco2.242
  13. Clin Exp Med. 2023 Apr 06.
    Overcoming anti-PD-1/PD-L1 immune checkpoint blockade resistance: the role of macrophage, neutrophils and mast cells in the tumor microenvironment.
    Louis Boafo Kwantwi.
      In recent years, the anti-PD-1/PD-L1 blockade has become a game changer in cancer treatment following the unprecedented response rate. Regardless of the substantial therapy efficacy across various cancer types, some patients do not still respond to these therapies, indicating that a deeper understanding of the mechanisms of anti-PD-1/PD-L1 resistance is highly important. To overcome such resistance, the tumor-induced immunosuppressive mechanisms have been focused and several suppressor cell populations in the tumor microenvironment have been identified. Among these cells, macrophages, neutrophils, and mast cells are known to play key roles in anti-PD-1/PD-L1 resistance. Hence, gaining control over these innate immune cells can open opportunities for breaking tumor resistance to immune checkpoint inhibitors. Herein, a summary of the role of macrophages, neutrophils, and mast cells in anti-PD-1/PD-L1 resistance has been described. Also, strategies to overcome their therapeutic resistance to anti-PD-1/PD-L1 have been discussed.
    Keywords:  Anti-PD-L1/PD-1; Immune checkpoint blockade; Tumor-associated macrophages; Tumor-associated mast cells; Tumor-associated neutrophils
    DOI:  https://doi.org/10.1007/s10238-023-01059-4
  14. Cancer Med. 2023 Apr 06.
    Integrative single-cell sequencing analysis distinguishes survival-associated cells from the breast cancer microenvironment.
    Ling Huang, Shijie Qin, Lingling Xia, Fei Ma, Liming Chen.
      BACKGROUND: Breast cancer shows a highly complex tumor microenvironment by containing various cell types. Identifying prognostic cell populations in the tumor microenvironment will improve the mechanistical understanding of breast cancer and facilitate the development of new breast cancer therapies by targeting the tumor microenvironment. The development of single-cell sequencing reveals various cell types, states, and lineages within the context of heterogenous breast tumors, but identifying phenotype-associated subpopulations is challenging.RESULTS: Here, we applied Scissor (single-cell identification of subpopulations with bulk Sample phenotype correlation) to integrate single cell and bulk data of breast cancer, and found that MHC-deficient tumor cells, FABP5+ macrophages, and COL1A1+ cancer-associated fibroblasts (CAFs) were detrimental to patient survival, while T cells and dendritic cells were the main protective cells. MHC-deficient tumor cells show strong downregulation of MHC expression for immune evasion by downregulating interferon and JAK-STATs signaling. FABP5+ macrophages show low antigen-presenting activity via associating with lipid metabolism. Our data suggest that COL1A1+ CAFs may block T-cell immune infiltration through cell interaction in breast tumor microenvironment.
    CONCLUSION: Taken together, our study reveals survival-associated subpopulations in breast tumor microenvironment. Importantly, subpopulations related to immune evasion of breast cancer is uncovered.
    Keywords:  breast cancer; immune evasion; prognostic cell; single-cell sequencing; tumor microenvironment
    DOI:  https://doi.org/10.1002/cam4.5892
  15. Biomaterials. 2023 Apr 01. pii: S0142-9612(23)00109-6. [Epub ahead of print]297 122101
    Mechano-modulation of T cells for cancer immunotherapy.
    Jeongeun Hyun, So Jung Kim, Sung-Dae Cho, Hae-Won Kim.
      Immunotherapy, despite its promise for future anti-cancer approach, faces significant challenges, such as off-tumor side effects, innate or acquired resistance, and limited infiltration of immune cells into stiffened extracellular matrix (ECM). Recent studies have highlighted the importance of mechano-modulation/-activation of immune cells (mainly T cells) for effective caner immunotherapy. Immune cells are highly sensitive to the applied physical forces and matrix mechanics, and reciprocally shape the tumor microenvironment. Engineering T cells with tuned properties of materials (e.g., chemistry, topography, and stiffness) can improve their expansion and activation ex vivo, and their ability to mechano-sensing the tumor specific ECM in vivo where they perform cytotoxic effects. T cells can also be exploited to secrete enzymes that soften ECM, thus increasing tumor infiltration and cellular therapies. Furthermore, T cells, such as chimeric antigen receptor (CAR)-T cells, genomic engineered to be spatiotemporally controllable by physical stimuli (e.g., ultrasound, heat, or light), can mitigate adverse off-tumor effects. In this review, we communicate these recent cutting-edge endeavors devoted to mechano-modulating/-activating T cells for effective cancer immunotherapy, and discuss future prospects and challenges in this field.
    Keywords:  Biophysical cues; Immunotherapy; Mechano-modulation; T cells; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.biomaterials.2023.122101
  16. Cancer Commun (Lond). 2023 Apr 02.
    Tumor microenvironment signaling and therapeutics in cancer progression.
    Anshika Goenka, Fatima Khan, Bhupender Verma, Priyanka Sinha, Crismita C Dmello, Manasi P Jogalekar, Prakash Gangadaran, Byeong-Cheol Ahn.
      Tumor development and metastasis are facilitated by the complex interactions between cancer cells and their microenvironment, which comprises stromal cells and extracellular matrix (ECM) components, among other factors. Stromal cells can adopt new phenotypes to promote tumor cell invasion. A deep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these interactions. In this review, we describe the tumor microenvironment (TME) components and associated therapeutics. We discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME, the immune checkpoints and immunosuppressive chemokines, and currently used inhibitors targeting these pathways. These include both intrinsic and non-autonomous tumor cell signaling pathways in the TME: protein kinase C (PKC) signaling, Notch, and transforming growth factor (TGF-β) signaling, Endoplasmic Reticulum (ER) stress response, lactate signaling, Metabolic reprogramming, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and Siglec signaling pathways. We also discuss the recent advances in Programmed Cell Death Protein 1 (PD-1), Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4), T-cell immunoglobulin mucin-3 (TIM-3) and Lymphocyte Activating Gene 3 (LAG3) immune checkpoint inhibitors along with the C-C chemokine receptor 4 (CCR4)- C-C class chemokines 22 (CCL22)/ and 17 (CCL17), C-C chemokine receptor type 2 (CCR2)- chemokine (C-C motif) ligand 2 (CCL2), C-C chemokine receptor type 5 (CCR5)- chemokine (C-C motif) ligand 3 (CCL3) chemokine signaling axis in the TME. In addition, this review provides a holistic understanding of the TME as we discuss the three-dimensional and microfluidic models of the TME, which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti-cancer therapies. We further discuss the systemic influences of gut microbiota in TME reprogramming and treatment response. Overall, this review provides a comprehensive analysis of the diverse and most critical signaling pathways in the TME, highlighting the associated newest and critical preclinical and clinical studies along with their underlying biology. We highlight the importance of the most recent technologies of microfluidics and lab-on-chip models for TME research and also present an overview of extrinsic factors, such as the inhabitant human microbiome, which have the potential to modulate TME biology and drug responses.
    Keywords:  3D-model; cancer therapy; gut microbiota; immune signaling; metabolism; signaling; tumor microenvironment
    DOI:  https://doi.org/10.1002/cac2.12416
  17. Biochem Pharmacol. 2023 Apr 05. pii: S0006-2952(23)00127-2. [Epub ahead of print] 115536
    Expressing IL-15/IL-18 and CXCR2 improve infiltration and survival of EGFRvIII-targeting CAR-T cells in breast cancer.
    Sun Ruixin, Liu Yifan, Wu Chuanlong, Zhou Min, Luo Hong, Du Guoxiu, Liu Zhengyang, Sun Yansha, Dong Yiwei, Su Jingwen, Fan Mingliang, Shi Bizhi, Jiang Hua, Li Zonghai.
      Previously, we have generated EGFRvIII-targeting CAR-T cells and brought hope for treating advanced breast cancer. However, EGFRvIII-targeting CAR-T cells were defined limited anti-tumor efficacy, which might be due to reduced accumulation, persistence of therapeutic T cells in tumor site of breast cancer. CXCLs were highly expressed in tumor environment of breast cancer and CXCR2 is the main receptor for CXCLs. Here, CXCR2 could significantly improve the trafficking and tumor specific accumulation of CAR-T cells both in vivo and in vitro. However, the anti-tumor effect of CXCR2 CAR-T cells were weaken which might be results of the apoptosis of T cells. Cytokines could stimulate Tcell proliferation, such as interleukin (IL)-15 and IL-18. Then, we generated CXCR2 CAR with synthetic IL-15 or IL-18 production. Co-expressing IL-15 or IL-18 could significantly suppress the exhaustion and apoptosis of T cells and enhanced the anti-tumor activity of CXCR2 CAR-T cells in vivo. Further, coexpression IL-15 or IL-18 in CXCR2 CAR-T cells did not cause toxicity. These findings provide a potential therapy strategy of co-expression IL-15 or IL-18 in CXCR2 CAR-T cells for the treatment of advancing breast cancer in the future.
    Keywords:  Breast cancer; CAR-T cells; CXCR2; Interleukin
    DOI:  https://doi.org/10.1016/j.bcp.2023.115536
  18. Biomed Pharmacother. 2023 Apr 04. pii: S0753-3322(23)00436-5. [Epub ahead of print]162 114648
    Current progress in chimeric antigen receptor-modified T cells for the treatment of metastatic breast cancer.
    Li Yin, Gui-Lai Chen, Zhuo Xiang, Yu-Lin Liu, Xing-Yu Li, Jing-Wang Bi, Qiang Wang.
      Breast cancer is the leading cancer in women. Around 20-30% breast cancer patients undergo invasion or metastasis after radical surgical resection and eventually die. Number of breast cancer patients show poor sensitivity toward treatments despite the advances in chemotherapy, endocrine therapy, and molecular targeted treatments. Therapeutic resistance and tumor recurrence or metastasis develop with the ongoing treatments. Conducive treatment strategies are thus required. Chimeric antigen receptor (CAR)-modified T-cell therapy has progressed as a part of tumor immunotherapy. However, CAR-T treatment has not been effective in solid tumors because of tumor microenvironment complexity, inhibitory effects of extracellular matrix, and lacking ideal tumor antigens. Herein, the prospects of CAR-T cell therapy for metastatic breast cancer are discussed, and the targets for CAR-T therapy in breast cancer (HER-2, C-MET, MSLN, CEA, MUC1, ROR1, EGFR) at clinical level are reviewed. Moreover, solutions are proposed for the challenges of breast cancer CAR-T therapy regarding off-target effects, heterogeneous antigen expression by tumor cells and immunosuppressive tumor microenvironment. Ideas for improving the therapeutics of CAR-T cell therapy in metastatic breast cancer are suggested.
    Keywords:  Chimeric antigen receptor-modified T-cells; Immunotherapy; Metastatic breast cancer; Tumor antigens
    DOI:  https://doi.org/10.1016/j.biopha.2023.114648
  19. Front Immunol. 2023 ;14 1113882
    The current landscape of CAR T-cell therapy for solid tumors: Mechanisms, research progress, challenges, and counterstrategies.
    Amin Daei Sorkhabi, Leila Mohamed Khosroshahi, Aila Sarkesh, Amirhossein Mardi, Ali Aghebati-Maleki, Leili Aghebati-Maleki, Behzad Baradaran.
      The successful outcomes of chimeric antigen receptor (CAR) T-cell therapy in treating hematologic cancers have increased the previously unprecedented excitement to use this innovative approach in treating various forms of human cancers. Although researchers have put a lot of work into maximizing the effectiveness of these cells in the context of solid tumors, few studies have discussed challenges and potential strategies to overcome them. Restricted trafficking and infiltration into the tumor site, hypoxic and immunosuppressive tumor microenvironment (TME), antigen escape and heterogeneity, CAR T-cell exhaustion, and severe life-threatening toxicities are a few of the major obstacles facing CAR T-cells. CAR designs will need to go beyond the traditional architectures in order to get over these limitations and broaden their applicability to a larger range of malignancies. To enhance the safety, effectiveness, and applicability of this treatment modality, researchers are addressing the present challenges with a wide variety of engineering strategies as well as integrating several therapeutic tactics. In this study, we reviewed the antigens that CAR T-cells have been clinically trained to recognize, as well as counterstrategies to overcome the limitations of CAR T-cell therapy, such as recent advances in CAR T-cell engineering and the use of several therapies in combination to optimize their clinical efficacy in solid tumors.
    Keywords:  CAR T-cell; challenges; chimeric antigen receptor; clinical trials; immunotherapy; solid tumors
    DOI:  https://doi.org/10.3389/fimmu.2023.1113882
  20. Acta Biochim Biophys Sin (Shanghai). 2023 Apr 25.
    Metabolic reprogramming of the ovarian cancer microenvironment in the development of antiangiogenic resistance.
    Huiran Yue, Xin Lu.
      Antiangiogenic therapies, such as treatment with bevacizumab, display modest survival benefits in ovarian cancer (OC) patients. After a transient response, the upregulation of compensatory proangiogenic pathways and the adoption of alternative vascularization processes lead to the development of resistance. Considering the high mortality rate of OC, there is an urgent need to uncover the underlying mechanisms of antiangiogenic resistance for the development of novel and effective treatment strategies. Recent investigations have confirmed that metabolic reprogramming in the tumor microenvironment (TME) exerts an essential effect on tumor aggressiveness and angiogenesis. In this review, we provide an overview of the metabolic crosstalk between OC and the TME, highlighting the regulatory mechanisms underlying the development of antiangiogenic resistance. Metabolic interventions may interrupt this complex and dynamic interactive network, providing a promising therapeutic option to improve clinical outcome in OC patients.
    Keywords:  antiangiogenic therapy; metabolism; ovarian cancer; tumor microenvironment
    DOI:  https://doi.org/10.3724/abbs.2023046
  21. Cancer Lett. 2023 Apr 04. pii: S0304-3835(23)00103-9. [Epub ahead of print] 216152
    Ferroptosis: Promising approach for cancer and cancer immunotherapy.
    Shuyue Zheng, Xin-Yuan Guan.
      Ferroptosis is the cell death induced by ferrous ions and lipid peroxidation accumulation in tumor cells. Targeting ferroptosis, which is regulated by various metabolic and immune elements, might become a novel strategy for anti-tumor therapy. In this review, we will focus on the mechanism of ferroptosis and its interaction with cancer and tumor immune microenvironment, especially for the relationship between immune cells and ferroptosis. Also, we will discuss the latest preclinical progress of the collaboration between the ferroptosis-targeted drugs and immunotherapy, and the best potential conditions for their combined use. It will present a future insight on the possible value of ferroptosis in cancer immunotherapy.
    Keywords:  Ferroptosis; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2023.216152
  22. Pathol Oncol Res. 2023 ;29 1610956
    NAD+ biosynthesis metabolism predicts prognosis and indicates immune microenvironment for breast cancer.
    Yuting Yang, Ze Wang, Mengqi He, Lihong Diao, Biyue Yu, Dong Li.
      The growing evidence implies that tumor cells need to increase NAD+ levels by upregulating NAD+ biosynthesis to satisfy their growth demand. NAD+ biosynthesis metabolism is implicated in tumor progression. Breast cancer (BC) is the most common malignant malignancy in the world. Nevertheless, the prognostic significance of NAD+ biosynthesis and its relationship with the tumor immune microenvironment in breast cancer still need further investigation. In this study, we obtained the mRNA expression data and clinical information of BC samples from public databases and calculated the level of NAD+ biosynthesis activity by single-sample gene set enrichment analysis (ssGSEA). We then explored the relationship between the NAD+ biosynthesis score, infiltrating immune cells, prognosis significance, immunogenicity and immune checkpoint molecules. The results demonstrated that patients with high NAD+ biosynthetic score displayed poor prognosis, high immune infiltration, high immunogenicity, elevated PD-L1 expression, and might more benefit from immunotherapy. Taken together, our studies not only deepened the understanding of NAD+ biosynthesis metabolism of breast cancer but also provided new insights into personalized treatment strategies and immunological therapies to improve the outcomes of breast cancer patients.
    Keywords:  NAD+ biosynthesis; breast cancer; immune microenvironment; immunotherapy; prognosis
    DOI:  https://doi.org/10.3389/pore.2023.1610956
  23. Front Physiol. 2023 ;14 1119095
    Interplay between stress and cancer-A focus on inflammation.
    Sanja Vignjević Petrinović, Maja S Milošević, Dragana Marković, Sanja Momčilović.
      Stress is an integral part of life. While acute responses to stress are generally regarded as beneficial in dealing with immediate threats, chronic exposure to threatening stimuli exerts deleterious effects and can be either a contributing or an aggravating factor for many chronic diseases including cancer. Chronic psychological stress has been identified as a significant factor contributing to the development and progression of cancer, but the mechanisms that link chronic stress to cancer remain incompletely understood. Psychological stressors initiate multiple physiological responses that result in the activation of the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic nervous system, and the subsequent changes in immune function. Chronic stress exposure disrupts the homeostatic communication between the neuroendocrine and immune systems, shifting immune signaling toward a proinflammatory state. Stress-induced chronic low-grade inflammation and a decline in immune surveillance are both implicated in cancer development and progression. Conversely, tumor-induced inflammatory cytokines, apart from driving a tumor-supportive inflammatory microenvironment, can also exert their biological actions distantly via circulation and therefore adversely affect the stress response. In this minireview, we summarize the current findings on the relationship between stress and cancer, focusing on the role of inflammation in stress-induced neuroendocrine-immune crosstalk. We also discuss the underlying mechanisms and their potential for cancer treatment and prevention.
    Keywords:  cancer; chronic stress; inflammation; microenvironment; proinflammatory cytokines
    DOI:  https://doi.org/10.3389/fphys.2023.1119095
  24. Genes Dis. 2023 Jan;10(1): 7-9
    Does burning fat make tumor immune hot? Discovery of CD47 overexpression by radiation induced fatty acid oxidation.
    Nian Jiang, Bowen Xie, Ming Fan, Jian Jian Li.
      Although extensively studied, it is unknown what is the major cellular energy driving tumor metastasis after anti-cancer radiotherapy. Metabolic reprogramming is one of the fundamental hallmarks in carcinogenesis and tumor progression featured with the increased glycolysis in solid tumors. However, accumulating evidence indicates that in addition to the rudimentary glycolytic pathway, tumor cells are capable of reactivating mitochondrial OXPHOS under genotoxic stress condition to meet the increasing cellular fuel demand for repairing and surviving anti-cancer radiation. Such dynamic metabolic rewiring may play a key role in cancer therapy resistance and metastasis. Interestingly, data from our group and others have demonstrated that cancer cells can re-activate mitochondrial oxidative respiration to boost an annexing energy to meet the increasing cellular fuel demand for tumor cells surviving genotoxic anti-cancer therapy with metastatic potential.
    Keywords:  CD47; Immune checkpoint; Immunotherapy; Metabolic rewiring; Radiation therapy; Tumor acquired resistance
    DOI:  https://doi.org/10.1016/j.gendis.2022.07.019
  25. Oncoimmunology. 2023 ;12(1): 2197360
    Beyond checkpoint inhibition: PD-1 cis-targeting of an IL-2Rβγ-biased interleukin-2 variant as a novel approach to build on checkpoint inhibition.
    Laura Codarri Deak, Masao Hashimoto, Pablo Umaña, Christian Klein.
      The immunocytokine PD1-IL2v was designed to overcome liabilities and improve efficacy of IL-2 therapies. PD1-IL2v preferentially targets PD-1+ T-cells and acts on antigen-specific stem-like PD-1+ TCF-1+ CD8+ T-cells expanding and differentiating them towards better effectors resulting in superior efficacy in LCMV chronic infection and tumor models compared to checkpoint inhibition.
    Keywords:  Eciskafusp alfa; IL-2; PD-1; PD1-IL2v; RG6279; TCF-1
    DOI:  https://doi.org/10.1080/2162402X.2023.2197360
  26. Front Oncol. 2023 ;13 1097983
    Immunotherapy for HER-2 positive breast cancer.
    Tingting Yang, Lihua Kang, Dan Li, Yanqiu Song.
      Immunotherapy is a developing treatment for advanced breast cancer. Immunotherapy has clinical significance for the treatment of triple-negative breast cancers and human epidermal growth factor receptor-2 positive (HER2+) breast cancers. As a proved effective passive immunotherapy, clinical application of the monoclonal antibodies trastuzumab, pertuzumab and T-DM1 (ado-trastuzumab emtansine) has significantly improved the survival of patients with HER2+ breast cancers. Immune checkpoint inhibitors that block programmed death receptor-1 and its ligand (PD-1/PD-L1) have also shown benefits for breast cancer in various clinical trials. Adoptive T-cell immunotherapies and tumor vaccines are emerging as novel approaches to treating breast cancer, but require further study. This article reviews recent advances in immunotherapy for HER2+ breast cancers.
    Keywords:  HER2+; active immunotherapy; adoptive T-cell immunotherapies; breast cancer; immune checkpoint inhibitors; passive immunotherapy
    DOI:  https://doi.org/10.3389/fonc.2023.1097983
  27. Front Immunol. 2023 ;14 1093716
    Pan-cancer analysis identifies PD-L2 as a tumor promotor in the tumor microenvironment.
    Jingfang Lv, Zheng Jiang, Junhu Yuan, Meng Zhuang, Xu Guan, Hengchang Liu, Yefeng Yin, Yiming Ma, Zheng Liu, Hongying Wang, Xishan Wang.
      Background: Programmed cell death protein 1 (PD-1) receptor has two ligands,programmed death-ligand 1 (PD-L1) and PD-L2. When compared with PD-L1, PD-L2 has not received much attention, and its role remains unclear.Methods: The expression profiles of pdcd1lg2 (PD-L2-encoding gene) mRNA and PD-L2 protein were analyzed using TCGA, ICGC, and HPA databases. Kaplan-Meier and Cox regression analyses were used to assess the prognostic significance of PD-L2. We used GSEA, Spearman's correlation analysis and PPI network to explore the biological functions of PD-L2. PD-L2-associated immune cell infiltration was evaluated using the ESTIMATE algorithm and TIMER 2.0. The expressions of PD-L2 in tumor-associated macrophages (TAMs) in human colon cancer samples, and in mice in an immunocompetent syngeneic setting were verified using scRNA-seq datasets, multiplex immunofluorescence staining, and flow cytometry. After fluorescence-activated cell sorting, flow cytometry and qRT-PCR and transwell and colony formation assays were used to evaluate the phenotype and functions of PD-L2+TAMs. Immune checkpoint inhibitors (ICIs) therapy prediction analysis was performed using TIDE and TISMO. Last, a series of targeted small-molecule drugs with promising therapeutic effects were predicted using the GSCA platform.
    Results: PD-L2 was expressed in all the common human cancer types and deteriorated outcomes in multiple cancers. PPI network and Spearman's correlation analysis revealed that PD-L2 was closely associated with many immune molecules. Moreover, both GSEA results of KEGG pathways and GSEA results for Reactome analysis indicated that PD-L2 expression played an important role in cancer immune response. Further analysis showed that PD-L2 expression was strongly associated with the infiltration of immune cells in tumor tissue in almost all cancer types, among which macrophages were the most positively associated with PD-L2 in colon cancer. According to the results mentioned above, we verified the expression of PD-L2 in TAMs in colon cancer and found that PD-L2+TAMs population was not static. Additionally, PD-L2+TAMs exhibited protumor M2 phenotype and increased the migration, invasion, and proliferative capacity of colon cancer cells. Furthermore, PD-L2 had a substantial predictive value for ICIs therapy cohorts.
    Conclusion: PD-L2 in the TME, especially expressed on TAMs, could be applied as a potential therapeutic target.
    Keywords:  PD-L2; colon cancer; immune checkpoint; pan-cancer analysis; tumor associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2023.1093716
  28. Biomed Pharmacother. 2023 Apr 01. pii: S0753-3322(23)00434-1. [Epub ahead of print]162 114646
    The impact of hypoxia on tumor-mediated bypassing anti-PD-(L)1 therapy.
    Keywan Mortezaee, Jamal Majidpoor, Ebrahim Kharazinejad.
      Extending the durability of response is the current focus in cancer immunotherapy with immune checkpoint inhibitors (ICIs). However, factors like non-immunogenic tumor microenvironment (TME) along with aberrant angiogenesis and dysregulated metabolic systems are negative contributors. Hypoxia is a key TME condition and a critical promoter of tumor hallmarks. It acts on immune and non-immune cells within TME in order for promoting immune evasion and therapy resistance. Extreme hypoxia is a major promoter of resistance to the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor therapy. Hypoxia inducible factor-1 (HIF-1) acts as a key mediator of hypoxia and a critical promoter of resistance to the anti-PD-(L)1. Targeting hypoxia or HIF-1 can thus be an effective strategy for reinvigoration of cellular immunity against cancer. Among various strategies presented so far, the key focus is over vascular normalization, which is an approach highly effective for reducing the rate of hypoxia, increasing drug delivery into the tumor area, and boosting the efficacy of anti-PD-(L)1.
    Keywords:  Heterogeneity; Hypoxia; Hypoxia inducible factor-1 (HIF-1); Immune checkpoint inhibitor (ICI); Programmed death-1 (PD-1); Programmed death-ligand 1 (PD-L1); Resistance
    DOI:  https://doi.org/10.1016/j.biopha.2023.114646
  29. Haematologica. 2023 Apr 06.
    IL-18 and VEGF-A trigger type 2 innate lymphoid cell accumulation and pro-tumoral function in chronic myeloid leukemia.
    Benedetta Fiordi, Valentina Salvestrini, Gabriele Gugliotta, Fausto Castagnetti, Antonio Curti, Daniel E Speiser, Emanuela Marcenaro, Camilla Jandus, Sara Trabanelli.
      Chronic Myeloid Leukemia (CML) is a hematologic malignancy associated to an unregulated growth of myeloid cells in Bone Marrow (BM) and Peripheral Blood (PB), characterized by the BCR-ABL1 translocation. Given the known cytokine impairment in the leukemic niche of CML, we investigated the impact of this microenvironmental dysregulation on Innate Lymphoid Cells (ILCs), whose role in cancer has recently emerged. Three ILC subsets are identified based on transcriptional profiles and cytokine secretion. We observed that IL-18 and VEGF-A are increased in CML patients' sera and that ILC2s are enriched in CML PB and BM. We found that IL-18 drives ILC2 proliferation and that CML ILC2s highly express CXCR4 and CXCR7 BM-homing receptors, potentially explaining their enrichment in PB and BM, respectively. Next, we showed that ILC2s are hyper-activated through a tumor-derived VEGF-A-dependent mechanism, which leads to higher IL-13 secretion. In response to IL-13, leukemic cells increase their clonogenic capacity. Finally, we discovered that the pro-tumoral axis involving VEGF-A, IL-18 and ILC2s was disrupted upon Tyrosine Kinase Inhibitors' (TKIs) treatment, normalizing the levels of all these players in CML patients responding to therapy. Overall, our study uncovers the involvement of ILC2s in CML progression, mediated by VEGF-A and IL-18.
    DOI:  https://doi.org/10.3324/haematol.2022.282140
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