bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023–07–09
37 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Modulation of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment by Natural Products.
  2. Targeting the Tumor-Tumor Microenvironment Crosstalk.
  3. Collagen architecture and signaling orchestrate cancer development.
  4. Targeting the metabolism and immune system in pancreatic ductal adenocarcinoma: Insights and future directions.
  5. Functional crosstalk and regulation of natural killer cells in tumor microenvironment: Significance and potential therapeutic strategies.
  6. Diet, nutrient supply, and tumor immune responses.
  7. miRNAs as key modulators between normal cells and tumor microenvironment interactions.
  8. Targeting PD-1/PD-L1 in cancer immunotherapy: An effective strategy for treatment of triple-negative breast cancer (TNBC) patients.
  9. Enhancing immunotherapy response in melanoma: myeloid-derived suppressor cells as a therapeutic target.
  10. Emerging role of deubiquitination modifications of programmed death-ligand 1 in cancer immunotherapy.
  11. Tumor-associated myeloid cells in cancer immunotherapy.
  12. The interplay between the DNA damage response and ectonucleotidases modulates tumor response to therapy.
  13. Rac and Cdc42 inhibitors reduce macrophage function in breast cancer preclinical models.
  14. Regulation of the tumor immune microenvironment by the Hippo Pathway: Implications for cancer immunotherapy.
  15. Ribonuclease 1 Enhances Antitumor Immunity against Breast Cancer by Boosting T cell Activation.
  16. Myeloid-derived suppressor cells (MDSCs): what do we currently know about the effect they have against anti-PD-1/PD-L1 therapies?
  17. [Progressin Tumor-Associated Macrophages in the Treatment of Pancreatic Cancer].
  18. Editorial: The role of immunophenotype in tumor immunotherapy response.
  19. NR1D1 stimulates antitumor immune responses in breast cancer by activating cGAS-STING signaling.
  20. Effect of infiltrating immune cells in tumor microenvironment on metastasis of hepatocellular carcinoma.
  21. Lymphatic vasculature in ovarian cancer.
  22. The emerging roles of SUMOylation in the tumor microenvironment and therapeutic implications.
  23. Novel PdPtCu Nanozymes for Reprogramming Tumor Microenvironment to Boost Immunotherapy Through Endoplasmic Reticulum Stress and Blocking IDO-Mediated Immune Escape.
  24. Traditional Chinese medicine inhibits PD-1/PD-L1 axis to sensitize cancer immunotherapy: a literature review.
  25. The Clinical Significance and Role of CXCL1 Chemokine in Gastrointestinal Cancers.
  26. Purinergic signalling in cancer therapeutic resistance: From mechanisms to targeting strategies.
  27. Stanniocalcin 1 promotes lung metastasis of breast cancer by enhancing EGFR-ERK-S100A4 signaling.
  28. Nonferrous Ferroptosis Inducer Manganese Molybdate Nanoparticles to Enhance Tumor Immunotherapy.
  29. Tissue Slice Culture and Analysis of Tumor-Associated Hyaluronan in Urothelial Carcinoma.
  30. Editorial: Hallmark of cancer: avoiding immune suppression.
  31. CAFs targeted ultrasound-responsive nanodroplets loaded V9302 and GLULsiRNA to inhibit melanoma growth via glutamine metabolic reprogramming and tumor microenvironment remodeling.
  32. Cancer-associated fibroblasts: from basic science to anticancer therapy.
  33. Harnessing the potential of CAR-T cell therapy: progress, challenges, and future directions in hematological and solid tumor treatments.
  34. Metformin ameliorates BMP2 induced adipocyte-like property in breast cancer cells.
  35. Etiology of super-enhancer reprogramming and activation in cancer.
  36. Hyperglycosylation of prosaposin in tumor DCs promotes immune escape in cancer.
  37. Uncovering the Role of CD4+ CAR T Cells in Cancer Immunotherapy.
  1. Arch Immunol Ther Exp (Warsz). 2023 Jul 06. 71(1): 17
    Modulation of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment by Natural Products.
    Jhon Jairo Calderon, Karol Prieto, Paola Lasso, Susana Fiorentino, Alfonso Barreto.
      During carcinogenesis, the microenvironment plays a fundamental role in tumor progression and resistance. This tumor microenvironment (TME) is characterized by being highly immunosuppressive in most cases, which makes it an important target for the development of new therapies. One of the most important groups of cells that orchestrate immunosuppression in TME is myeloid-derived suppressor cells (MDSCs), which have multiple mechanisms to suppress the immune response mediated by T lymphocytes and thus protect the tumor. In this review, we will discuss the importance of modulating MDSCs as a therapeutic target and how the use of natural products, due to their multiple mechanisms of action, can be a key alternative for modulating these cells and thus improve response to therapy in cancer patients.
    Keywords:  Cancer; MDSCs; Myeloid-derived suppressor cells; Natural products; Phytotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s00005-023-00681-0
  2. Expert Opin Ther Targets. 2023 Jul 04. 1-11
    Targeting the Tumor-Tumor Microenvironment Crosstalk.
    Sunil S Badve, Yesim Gökmen-Polar.
       INTRODUCTION: Cancer development and progression is a complex process influenced by co-evolution of the cancer cells and their microenvironment. However, traditional anti-cancer therapy is mostly targeted toward cancer cells. To improve the efficacy of cancer drugs, the complex interactions between the tumor (T) and the tumor microenvironment (TME) should be considered while developing therapeutics.
    AREAS COVERED: The present review article will discuss the components of T-TME as well as the potential to co-target these two distinct elements. We document that these approaches have resulted in success in preventing tumor progression and metastasis, albeit in animal models in some cases. Lastly, it is important to consider the tissue context and tumor type as these could significantly modify the role of these molecules/pathways and hence the overall likelihood of response. Furthermore, we discuss the potential strategies to target the components of tumor microenvironment in anti-cancer therapy. PubMed and ClinicalTrials.gov was searched through May 2023.
    EXPERT OPINION: The tumor-tumor microenvironment cross talk and heterogeneity are major mechanisms conferring resistance to standard of care. Better understanding of the tissue specific T-TME interactions and dual targeting has the promise of improving cancer control and clinical outcomes.
    Keywords:  Tumor; Tumor microenvironment; cancer progression; dual targeting; interactions; metastasis
    DOI:  https://doi.org/10.1080/14728222.2023.2230362
  3. Trends Cancer. 2023 Jul 01. pii: S2405-8033(23)00103-6. [Epub ahead of print]
    Collagen architecture and signaling orchestrate cancer development.
    Hua Su, Michael Karin.
      The tumor microenvironment (TME) controls tumor progression and maintenance. Accordingly, tumor-centric cancer treatment must adjust to being more holistic and TME-centric. Collagens are the most abundant TME proteins, and their dynamic remodeling profoundly affects both TME architecture and tumor development. Recent evidence shows that in addition to being structural elements, collagens are an important source of nutrients and decisive growth controlling and immunoregulatory signals. This review focuses on macropinocytosis-dependent collagen support of cancer cell metabolism and the role of collagen fiber remodeling and trimer heterogeneity in control of tumor bioenergetics, growth, progression, and response to therapy. If properly translated, these basic advances may alter the future of cancer treatment.
    Keywords:  DDR1; LAIR1; collagen; immunity; macropinocytosis; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2023.06.002
  4. Cytokine Growth Factor Rev. 2023 Jun 30. pii: S1359-6101(23)00029-1. [Epub ahead of print]
    Targeting the metabolism and immune system in pancreatic ductal adenocarcinoma: Insights and future directions.
    Dhana Sekhar Reddy Bandi, Sujith Sarvesh, Batoul Farran, Ganji Purnachandra Nagaraju, Bassel F El-Rayes.
      Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), presents a challenging landscape due to its complex nature and the highly immunosuppressive tumor microenvironment (TME). This immunosuppression severely limits the effectiveness of immune-based therapies. Studies have revealed the critical role of immunometabolism in shaping the TME and influencing PDAC progression. Genetic alterations, lysosomal dysfunction, gut microbiome dysbiosis, and altered metabolic pathways have been shown to modulate immunometabolism in PDAC. These metabolic alterations can significantly impact immune cell functions, including T-cells, myeloid-derived suppressor cells (MDSCs), and macrophages, evading anti-tumor immunity. Advances in immunotherapy offer promising avenues for overcoming immunosuppressive TME and enhancing patient outcomes. This review highlights the challenges and opportunities for future research in this evolving field. By exploring the connections between immunometabolism, genetic alterations, and the microbiome in PDAC, it is possible to tailor novel approaches capable of improving immunotherapy outcomes and addressing the limitations posed by immunosuppressive TME. Ultimately, these insights may pave the way for improved treatment options and better outcomes for PDAC patients.
    Keywords:  Immunometabolism; Immunotherapy; Metabolic pathways; Pancreatic ductal adenocarcinoma; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cytogfr.2023.06.006
  5. Genes Dis. 2023 May;10(3): 990-1004
    Functional crosstalk and regulation of natural killer cells in tumor microenvironment: Significance and potential therapeutic strategies.
    Liping Wang, Zhe Chen, Guohong Liu, Yunbao Pan.
      Natural killer (NK) cells eliminate a large variety of tumor cells and abnormal cells. However, NK cells in the tumor microenvironment (TME) are often functionally depleted. A few subsets of NK cells even promote tumor growth. This study reviewed the biological properties of NK cells, the dynamic phenotypic changes of NK cells in the TME, and the communication between NK cells and other immune and nonimmune cells.
    Keywords:  Cellular communication; Immune checkpoints; Immunotherapy; Natural killer cells; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.gendis.2022.07.009
  6. Trends Cancer. 2023 Jul 01. pii: S2405-8033(23)00104-8. [Epub ahead of print]
    Diet, nutrient supply, and tumor immune responses.
    Claire L McIntyre, Ayantu Temesgen, Lydia Lynch.
      Nutrients are essential for cell function. Immune cells operating in the complex tumor microenvironment (TME), which has a unique nutrient composition, face challenges of adapting their metabolism to support effector functions. We discuss the impact of nutrient availability on immune function in the tumor, competition between immune cells and tumor cells for nutrients, and how this is altered by diet. Understanding which diets can promote antitumor immune responses could open a new era of treatment, where dietary modifications can be used as an adjunct to boost the success of existing cancer therapies.
    Keywords:  T cells; cancer; diet; immune cells; metabolism; obesity
    DOI:  https://doi.org/10.1016/j.trecan.2023.06.003
  7. Chem Biol Drug Des. 2023 Jul 04.
    miRNAs as key modulators between normal cells and tumor microenvironment interactions.
    Shabnam Mohammadi Nour, Nadia Abbasi, Sima Sadi, Navid Ravan, Ali Alipourian, Mahsa Yarizadeh, Asma Soofi, Ali Ataei, Pooya M Tehrany.
      The tumor microenvironment (TME) is well-defined target for understanding tumor progression and various cell types. Major elements of the tumor microenvironment are the followings: endothelial cells, fibroblasts, signaling molecules, extracellular matrix, and infiltrating immune cells. MicroRNAs (miRNAs) are a group of small noncoding RNAs with major functions in the gene expression regulation at post-transcriptional level that have also appeared to exerts key functions in the cancer initiation/progression in diverse biological processes and the tumor microenvironment. This study summarized various roles of miRNAs in the complex interactions between the tumor and normal cells in their microenvironment.
    Keywords:  cancer; colon cancer; microRNA; tumor microenvironment
    DOI:  https://doi.org/10.1111/cbdd.14285
  8. Genes Dis. 2023 Jul;10(4): 1318-1350
    Targeting PD-1/PD-L1 in cancer immunotherapy: An effective strategy for treatment of triple-negative breast cancer (TNBC) patients.
    Sunny Kumar, Mouli Chatterjee, Pratyasha Ghosh, Kirat K Ganguly, Malini Basu, Mrinal K Ghosh.
      Maintaining the balance between eliciting immune responses against foreign proteins and tolerating self-proteins is crucial for maintenance of homeostasis. The functions of programmed death protein 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1) are to inhibit immune responses so that over-reacting immune cells does not cause any damage to its own body cells. However, cancer cells hijack this mechanism to attenuate immune cells functions and create an immunosuppressive environment that fuel their continuous growth and proliferation. Over the past few years' rapid development in cancer immunotherapy has opened a new avenue in cancer treatment. Blockade of PD-1 and PD-L1 has become a potential strategy that rescue the functions of immune cells to fight against cancer with high efficacy. Initially, immune checkpoint monotherapies were not very successful, making breast cancer less immunogenic. Although, recent reports support the presence of tumor infiltrating lymphocytes (TILs) in breast cancer that make it favorable for PD-1/PD-L1 mediated immunotherapy, which is effective in PD-L1 positive patients. Recently, anti-PD-1 (pembrolizumab) and anti-PD-L1 (atezolizumab) gets FDA approval for breast cancer treatment and make PD-1/PD-L1 immunotherapy is meaningful for further research. Likewise, this article gathered understanding of PD-1 and PD-L1 in recent years, their signaling networks, interaction with other molecules, regulations of their expressions and functions in both normal and tumor tissue microenvironments are crucial to find and design therapeutic agents that block this pathway and improve the treatment efficacy. Additionally, authors collected and highlighted most of the important clinical trial reports on monotherapy and combination therapy.
    Keywords:  Breast cancer; Cancer; Clinical trial; Immunotherapy; PD-1/PD-L1; TNBC
    DOI:  https://doi.org/10.1016/j.gendis.2022.07.024
  9. J Clin Invest. 2023 07 03. pii: e170762. [Epub ahead of print]133(13):
    Enhancing immunotherapy response in melanoma: myeloid-derived suppressor cells as a therapeutic target.
    Feyza Gul Ozbay Kurt, Samantha Lasser, Ihor Arkhypov, Jochen Utikal, Viktor Umansky.
      Despite the remarkable success of immune checkpoint inhibitors (ICIs) in melanoma treatment, resistance to them remains a substantial clinical challenge. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of myeloid cells that can suppress antitumor immune responses mediated by T and natural killer cells and promote tumor growth. They are major contributors to ICI resistance and play a crucial role in creating an immunosuppressive tumor microenvironment. Therefore, targeting MDSCs is considered a promising strategy to improve the therapeutic efficacy of ICIs. This Review describes the mechanism of MDSC-mediated immune suppression, preclinical and clinical studies on MDSC targeting, and potential strategies for inhibiting MDSC functions to improve melanoma immunotherapy.
    DOI:  https://doi.org/10.1172/JCI170762
  10. Front Immunol. 2023 ;14 1228200
    Emerging role of deubiquitination modifications of programmed death-ligand 1 in cancer immunotherapy.
    Yao Jiang, Kai Hong, Yingchao Zhao, Kai Xu.
      Immune evasion is essential for carcinogenesis and cancer progression. Programmed death-ligand 1 (PD-L1), a critical immune checkpoint molecule, interacts with programmed death receptor-1 (PD-1) on immune cells to suppress anti-tumor immune responses. In the past decade, antibodies targeting PD-1/PD-L1 have tremendously altered cancer treatment paradigms. Post-translational modifications have been reported as key regulators of PD-L1 expression. Among these modifications, ubiquitination and deubiquitination are reversible processes that dynamically control protein degradation and stabilization. Deubiquitinating enzymes (DUBs) are responsible for deubiquitination and have emerged as crucial players in tumor growth, progression, and immune evasion. Recently, studies have highlighted the participation of DUBs in deubiquitinating PD-L1 and modulating its expression. Here, we review the recent developments in deubiquitination modifications of PD-L1 and focus on the underlying mechanisms and effects on anti-tumor immunity.
    Keywords:  cancer immunotherapy; deubiquitinating enzymes; deubiquitination; post-translational modification; programmed death-ligand-1 (PD-L1)
    DOI:  https://doi.org/10.3389/fimmu.2023.1228200
  11. J Hematol Oncol. 2023 Jul 06. 16(1): 71
    Tumor-associated myeloid cells in cancer immunotherapy.
    Xinyu Cheng, Huilan Wang, Zhongyu Wang, Bo Zhu, Haixia Long.
      Tumor-associated myeloid cells (TAMCs) are among the most important immune cell populations in the tumor microenvironment, and play a significant role on the efficacy of immune checkpoint blockade. Understanding the origin of TAMCs was found to be the essential to determining their functional heterogeneity and, developing cancer immunotherapy strategies. While myeloid-biased differentiation in the bone marrow has been traditionally considered as the primary source of TAMCs, the abnormal differentiation of splenic hematopoietic stem and progenitor cells, erythroid progenitor cells, and B precursor cells in the spleen, as well as embryo-derived TAMCs, have been depicted as important origins of TAMCs. This review article provides an overview of the literature with a focus on the recent research progress evaluating the heterogeneity of TAMCs origins. Moreover, this review summarizes the major therapeutic strategies targeting TAMCs with heterogeneous sources, shedding light on their implications for cancer antitumor immunotherapies.
    Keywords:  Cancer immunotherapy; Immune checkpoint blockade; Immune evasion; Myelopoiesis; Tumor associated myeloid cells; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13045-023-01473-x
  12. Sci Immunol. 2023 Jul 14. 8(85): eabq3015
    The interplay between the DNA damage response and ectonucleotidases modulates tumor response to therapy.
    John Stagg, Encouse Golden, Erik Wennerberg, Sandra Demaria.
      The extracellular nucleoside adenosine reduces tissue inflammation and is generated by irreversible dephosphorylation of adenosine monophosphate (AMP) mediated by the ectonucleotidase CD73. The pro-inflammatory nucleotides adenosine triphosphate, nicotinamide adenine dinucleotide, and cyclic guanosine -monophosphate-AMP (cGAMP), which are produced in the tumor microenvironment (TME) during therapy-induced immunogenic cell death and activation of innate immune signaling, can be converted into AMP by ectonucleotidases CD39, CD38, and CD203a/ENPP1. Thus, ectonucleotidases shape the TME by converting immune-activating signals into an immunosuppressive one. Ectonucleotidases also hinder the ability of therapies including radiation therapy, which enhance the release of pro-inflammatory nucleotides in the extracellular milieu, to induce immune-mediated tumor rejection. Here, we review the immunosuppressive effects of adenosine and the role of different ectonucleotidases in modulating antitumor immune responses. We discuss emerging opportunities to target adenosine generation and/or its ability to signal via adenosine receptors expressed by immune and cancer cells in the context of combination immunotherapy and radiotherapy.
    DOI:  https://doi.org/10.1126/sciimmunol.abq3015
  13. Front Oncol. 2023 ;13 1152458
    Rac and Cdc42 inhibitors reduce macrophage function in breast cancer preclinical models.
    Anamaris Torres-Sanchez, Michael Rivera-Robles, Linette Castillo-Pichardo, Magaly Martínez-Ferrer, Stephanie M Dorta-Estremera, Suranganie Dharmawardhane.
       Background: Metastatic disease lacks effective treatments and remains the primary cause of mortality from epithelial cancers, especially breast cancer. The metastatic cascade involves cancer cell migration and invasion and modulation of the tumor microenvironment (TME). A viable anti-metastasis strategy is to simultaneously target the migration of cancer cells and the tumor-infiltrating immunosuppressive inflammatory cells such as activated macrophages, neutrophils, and myeloid-derived suppressor cells (MDSC). The Rho GTPases Rac and Cdc42 are ideal molecular targets that regulate both cancer cell and immune cell migration, as well as their crosstalk signaling at the TME. Therefore, we tested the hypothesis that Rac and Cdc42 inhibitors target immunosuppressive immune cells, in addition to cancer cells. Our published data demonstrate that the Vav/Rac inhibitor EHop-016 and the Rac/Cdc42 guanine nucleotide association inhibitor MBQ-167 reduce mammary tumor growth and prevent breast cancer metastasis from pre-clinical mouse models without toxic effects.
    Methods: The potential of Rac/Cdc42 inhibitors EHop-016 and MBQ-167 to target macrophages was tested in human and mouse macrophage cell lines via activity assays, MTT assays, wound healing, ELISA assays, and phagocytosis assays. Immunofluorescence, immunohistochemistry, and flow cytometry were used to identify myeloid cell subsets from tumors and spleens of mice following EHop-016 or MBQ-167 treatment.
    Results: EHop-016 and MBQ-167 inhibited Rac and Cdc42 activation, actin cytoskeletal extensions, migration, and phagocytosis without affecting macrophage cell viability. Rac/Cdc42 inhibitors also reduced tumor- infiltrating macrophages and neutrophils in tumors of mice treated with EHop-016, and macrophages and MDSCs from spleens and tumors of mice with breast cancer, including activated macrophages and monocytes, following MBQ-167 treatment. Mice with breast tumors treated with EHop-016 significantly decreased the proinflammatory cytokine Interleukin-6 (IL-6) from plasma and the TME. This was confirmed from splenocytes treated with lipopolysaccharide (LPS) where EHop-016 or MBQ-167 reduced IL-6 secretion in response to LPS.
    Conclusion: Rac/Cdc42 inhibition induces an antitumor environment via inhibition of both metastatic cancer cells and immunosuppressive myeloid cells in the TME.
    Keywords:  Cdc42; EHop-016; MBQ-167; Rac; breast cancer; macrophage function; myeloid derived suppressor cells (MDSCs)
    DOI:  https://doi.org/10.3389/fonc.2023.1152458
  14. Int Immunopharmacol. 2023 Jun 30. pii: S1567-5769(23)00912-8. [Epub ahead of print]122 110586
    Regulation of the tumor immune microenvironment by the Hippo Pathway: Implications for cancer immunotherapy.
    Chang Liu, Yang Song, DeMing Li, Biao Wang.
      The tumor immune microenvironment (TIME) is a dynamic and complex ecosystem consisting of immune cells, stromal cells, and tumor cells. It plays a crucial role in shaping cancer progression and treatment outcomes. Notably, tumor-associated immune cells are key regulators within the TIME, influencing immune responses and therapeutic efficacy. The Hippo pathway is a critical signaling pathway involved in the TIME and cancer progression. In this review, we provide an overview of the Hippo pathway's role in the TIME, focusing on its interactions with immune cells and their implications in cancer biology and therapy. Specifically, we discuss the involvement of the Hippo pathway in regulating T-cell function, macrophage polarization, B-cell differentiation, MDSC activity, and dendritic cell-mediated immune responses. Furthermore, we explore its influence on PD-L1 expression in lymphocytes and its potential as a therapeutic target. While recent progress has been made in understanding the Hippo pathway's molecular mechanisms, challenges remain in deciphering its context-dependent effects in different cancers and identifying predictive biomarkers for targeted therapies. By elucidating the intricate crosstalk between the Hippo pathway and the TME, we aim to contribute to the development of innovative strategies for cancer treatment.
    Keywords:  Hippo pathway; Immunotherapy; Tumor immune microenvironments
    DOI:  https://doi.org/10.1016/j.intimp.2023.110586
  15. Int J Biol Sci. 2023 ;19(10): 2957-2973
    Ribonuclease 1 Enhances Antitumor Immunity against Breast Cancer by Boosting T cell Activation.
    Ying-Nai Wang, Heng-Huan Lee, Zhou Jiang, Li-Chuan Chan, Gabriel N Hortobagyi, Dihua Yu, Mien-Chie Hung.
      The secretory enzyme human ribonuclease 1 (RNase1) is involved in innate immunity and anti-inflammation, achieving host defense and anti-cancer effects; however, whether RNase1 contributes to adaptive immune response in the tumor microenvironment (TME) remains unclear. Here, we established a syngeneic immunocompetent mouse model in breast cancer and demonstrated that ectopic RNase1 expression significantly inhibited tumor progression. Overall changes in immunological profiles in the mouse tumors were analyzed by mass cytometry and showed that the RNase1-expressing tumor cells significantly induced CD4+ Th1 and Th17 cells and natural killer cells and reduced granulocytic myeloid-derived suppressor cells, supporting that RNase1 favors an antitumor TME. Specifically, RNase1 increased expression of T cell activation marker CD69 in a CD4+ T cell subset. Notably, analysis of cancer-killing potential revealed that T cell-mediated antitumor immunity was enhanced by RNase1, which further collaborated with an EGFR-CD3 bispecific antibody to protect against breast cancer cells across molecular subtypes. Our results uncover a tumor-suppressive role of RNase1 through adaptive immune response in breast cancer in vivo and in vitro, providing a potential treatment strategy of combining RNase1 with cancer immunotherapies for immunocompetent patients.
    Keywords:  T cell activity; antitumor immunity; breast cancer; ribonuclease 1; tumor microenvironment; tumor-infiltrating immune cells
    DOI:  https://doi.org/10.7150/ijbs.84592
  16. Ecancermedicalscience. 2023 ;17 1556
    Myeloid-derived suppressor cells (MDSCs): what do we currently know about the effect they have against anti-PD-1/PD-L1 therapies?
    Ronald Sergio Limón Tellez, Lucia Reynolds, Miguel A Piris.
      Recent advances in cancer treatment such as PD-1/PD-L1 checkpoint inhibitors have prompted multiple research studies to determine all of the factors that influence response or failure to these new treatments. One of those identified factors is myeloid-derived suppressor cells (MDSCs). These cells were identified and described for the first time in 2007 in laboratory mice and cancer patients. Previous studies showed that a greater number of MDSCs was directly related to a greater tumour volume. There are two clearly identified subpopulations: Mononuclear-type myeloid-derived suppressor cells (M-MDSCs) and polymorphonuclear (PMN-MDSCs). These cell population subtypes play a very important role, depending on the type of cancer, since they have the particularity of expressing PD-L1, which interacts with PD-1, inhibiting the expansion of cytotoxic T lymphocytes, promoting resistance to these treatments.
    Keywords:  Myeloid-derived suppressor cells (MDSCs); PD-1 and PD-L1; immunotherapy; tumour microenvironment
    DOI:  https://doi.org/10.3332/ecancer.2023.1556
  17. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2023 Jun;45(3): 471-478
    [Progressin Tumor-Associated Macrophages in the Treatment of Pancreatic Cancer].
    Ke Zhang, Ya-Han Qin, Jie Shen, Meng-Yu Zhang, Mei-Yu Peng.
      Pancreatic cancer is one of the digestive system tumors with a high degree of malignancy,and most of the patients are diagnosed in advanced stages.Because of limited available therapies,the mortality of this disease remains high.Tumor-associated macrophages(TAM),the main immune cells in the tumor microenvironment,are involved in the regulation of the occurrence and development of pancreatic cancer.Specifically,TAM are involved in the proliferation,invasion,immune escape,and chemoresistance of pancreatic cancer cells,demonstrating potential in the targeted therapy of pancreatic cancer.In this paper,we summarize the TAM-based therapies including consuming TAM,reprogramming TAM,dynamic imaging of TAM with nanoprobes,and regulating the phagocytic ability of TAM for pancreatic cancer,aiming to provide a theoretical basis for developing new therapies for pancreatic cancer.
    Keywords:  immunotherapy; pancreatic cancer; targeted therapy; tumor-associated macrophages
    DOI:  https://doi.org/10.3881/j.issn.1000-503X.15282
  18. Front Genet. 2023 ;14 1222064
    Editorial: The role of immunophenotype in tumor immunotherapy response.
    Yujuan Qin, Jian Song.
      
    Keywords:  bioinformatics; diagnosis; immunotherapy; prognosis; tumor microenvironment
    DOI:  https://doi.org/10.3389/fgene.2023.1222064
  19. Cancer Res. 2023 Jul 03. pii: CAN-23-0329. [Epub ahead of print]
    NR1D1 stimulates antitumor immune responses in breast cancer by activating cGAS-STING signaling.
    Na-Lee Ka, Mi Kyung Park, Seung-Su Kim, Yoon Jeon, Sewon Hwang, Sun Mi Kim, Ga Young Lim, Ho Lee, Mi-Ock Lee.
      Potentiating antitumor immunity is a promising therapeutic approach for treating a variety of cancers, including breast cancer. One potential strategy to promote antitumor immunity is targeting DNA damage response. Given that the nuclear receptor NR1D1 (also known as REV-ERBα) inhibits DNA repair in breast cancer cells, we explored the role of NR1D1 in antitumor CD8+ T cell responses. First, deletion of Nr1d1 in MMTV-PyMT transgenic mice resulted in increased tumor growth and lung metastasis. Orthotopic allograft experiments suggested that loss of Nr1d1 in tumor cells rather than in stromal cells played a prominent role in increasing tumor progression. Comprehensive transcriptome analyses revealed that biological processes including type I interferon (IFN) signaling and T cell-mediated immune responses were associated with NR1D1. Indeed, the expression of type I IFNs and infiltration of CD8+ T cells and natural killer cells in tumors were suppressed in Nr1d1-/-;MMTV-PyMT mice. Mechanistically, NR1D1 promoted DNA damage-induced accumulation of cytosolic DNA fragments and activated cGAS-STING signaling, which increased the production of type I IFNs and downstream chemokines CCL5 and CXCL10. Pharmacological activation of NR1D1 by its ligand, SR9009, enhanced type I IFN-mediated antitumor immunity accompanied by the suppression of tumor progression and lung metastasis. Taken together, these findings reveal the critical role of NR1D1 in enhancing antitumor CD8+ T cell responses, suggesting that NR1D1 may be a good therapeutic target for breast cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0329
  20. Cell Oncol (Dordr). 2023 Jul 06.
    Effect of infiltrating immune cells in tumor microenvironment on metastasis of hepatocellular carcinoma.
    Yiwen Chen, Yuhang Zhou, Ziyang Yan, Peilin Tong, Qiang Xia, Kang He.
      Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent human malignancies, leading to poor prognosis due to its high recurrence and metastasis rates. In recent years it has become increasingly evident that the tumor microenvironment (TME) plays an important role in tumor progression and metastasis. Tumor microenvironment (TME) refers to the complex tissue environment of tumor occurrence and development. Here, we summarize the development of HCC and the role of cellular and non-cellular components of the TME in the metastasis HCC, with particular reference to tumor-infiltrating immune cells. We also discuss some of the possible therapeutic targets for the TME and the future prospectives of this evolving field. SIGNIFICANCE: This review provides a comprehensive analysis of the role of the infiltrating immune cells in TME in the metastasis of HCC and highlights the future outlook for targeted therapy of the TME in the context of recent experiments revealing a number of therapeutic targets targeting the TME.
    Keywords:  HCC; Infiltrating immune cells; Metastasis; NK cells; TAM; TAN; TME
    DOI:  https://doi.org/10.1007/s13402-023-00841-6
  21. Biochim Biophys Acta Rev Cancer. 2023 Jul 05. pii: S0304-419X(23)00099-9. [Epub ahead of print] 188950
    Lymphatic vasculature in ovarian cancer.
    Sarit Pal, Sramana Bhowmick, Anurag Sharma, Jorge A Sierra-Fonseca, Susmita Mondal, Favour Afolabi, Debarshi Roy.
      Ovarian cancer (OVCA) is the second most common gynecological cancer and one of the leading causes of cancer related mortality among women. Recent studies suggest that among ovarian cancer patients at least 70% of the cases experience the involvement of lymph nodes and metastases through lymphatic vascular network. However, the impact of lymphatic system in the growth, spread and the evolution of ovarian cancer, its contribution towards the landscape of ovarian tissue resident immune cells and their metabolic responses is still a major knowledge gap. In this review first we present the epidemiological aspect of the OVCA, the lymphatic architecture of the ovary, we discuss the role of lymphatic circulation in regulation of ovarian tumor microenvironment, metabolic basis of the upregulation of lymphangiogenesis which is often observed during progression of ovarian metastasis and ascites development. Further we describe the implication of several mediators which influence both lymphatic vasculature as well as ovarian tumor microenvironment and conclude with several therapeutic strategies for targeting lymphatic vasculature in ovarian cancer progression in present day.
    Keywords:  Lymphatics; Metabolism; Microenvironment; Ovarian cancer
    DOI:  https://doi.org/10.1016/j.bbcan.2023.188950
  22. Exp Hematol Oncol. 2023 Jul 06. 12(1): 58
    The emerging roles of SUMOylation in the tumor microenvironment and therapeutic implications.
    Yunru Gu, Yuan Fang, Xi Wu, Tingting Xu, Tong Hu, Yangyue Xu, Pei Ma, Qiang Wang, Yongqian Shu.
      Tumor initiation, progression, and response to therapies depend to a great extent on interactions between malignant cells and the tumor microenvironment (TME), which denotes the cancerous/non-cancerous cells, cytokines, chemokines, and various other factors around tumors. Cancer cells as well as stroma cells can not only obtain adaption to the TME but also sculpt their microenvironment through a series of signaling pathways. The post-translational modification (PTM) of eukaryotic cells by small ubiquitin-related modifier (SUMO) proteins is now recognized as a key flexible pathway. Proteins involved in tumorigenesis guiding several biological processes including chromatin organization, DNA repair, transcription, protein trafficking, and signal conduction rely on SUMOylation. The purpose of this review is to explore the role that SUMOylation plays in the TME formation and reprogramming, emphasize the importance of targeting SUMOylation to intervene in the TME and discuss the potential of SUMOylation inhibitors (SUMOi) in ameliorating tumor prognosis.
    Keywords:  Clinical implications; Hypoxia; Immune response; Inflammation; Metabolism; Post-translational modification; SUMOylation; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s40164-023-00420-3
  23. Small. 2023 Jul 02. e2303596
    Novel PdPtCu Nanozymes for Reprogramming Tumor Microenvironment to Boost Immunotherapy Through Endoplasmic Reticulum Stress and Blocking IDO-Mediated Immune Escape.
    Yulin Xie, Man Wang, Yanrong Qian, Lei Li, Qianqian Sun, Minghong Gao, Chunxia Li.
      Breaking immunosuppressive tumor microenvironment (TME) has unique effects on inhibiting tumor growth and recurrence. Here, an endoplasmic reticulum (ER) targeted PdPtCu nanozyme (PNBCTER ) is prepared to boost immunotherapy. First, PNBCTER has three kinds of enzyme activities, including catalase (CAT), glutathione oxidase (GSHOx), and peroxidase (POD)-like activities, which can reshape the TME. Second, PNBCTER kills tumor cells by photodynamic therapy (PDT) and photothermal therapy (PTT). Third, guided by TER , PNBCTER not only realizes the combination therapy of PDT, PTT and chemodynamic therapy (CDT), but also damages the ER of tumor cells and actives antitumor immune response, which breaks through the immune blockade of TME. Finally, the NLG919 blocks the tryptophan/kynurenine immune escape pathway and reverses the immunosuppressive TME. The strategy that reshaping the TME by enzyme catalysis and breaking immunosuppression provides a novel way for the application of combination therapy in tumor.
    Keywords:  combination therapy; endoplasmic reticulum targeting; immune checkpoint inhibitors; immunogenic cell death; noble metal nanozyme
    DOI:  https://doi.org/10.1002/smll.202303596
  24. Front Oncol. 2023 ;13 1168226
    Traditional Chinese medicine inhibits PD-1/PD-L1 axis to sensitize cancer immunotherapy: a literature review.
    Huilan Zheng, Gang Wang, Ming Liu, Hongbin Cheng.
      The Programmed death-1 (PD-1) and its programmed death-ligand 1 (PD-L1) comprise the PD-1/PD-L1 axis and maintain tumor immune evasion. Cancer immunotherapy based on anti-PD-1/PD-L1 antibodies is the most promising anti-tumor treatment available but is currently facing the thorny problem of unsatisfactory outcomes. Traditional Chinese Medicine (TCM), with its rich heritage of Chinese medicine monomers, herbal formulas, and physical therapies like acupuncture, moxibustion, and catgut implantation, is a multi-component and multi-target system of medicine known for enhancing immunity and preventing the spread of disease. TCM is often used as an adjuvant therapy for cancer in clinical practices, and recent studies have demonstrated the synergistic effects of combining TCM with cancer immunotherapy. In this review, we examined the PD-1/PD-L1 axis and its role in tumor immune escape while exploring how TCM therapies can modulate the PD-1/PD-L1 axis to improve the efficacy of cancer immunotherapy. Our findings suggest that TCM therapy can enhance cancer immunotherapy by reducing the expression of PD-1 and PD-L1, regulating T-cell function, improving the tumor immune microenvironment, and regulating intestinal flora. We hope this review may serve as a valuable resource for future studies on the sensitization of immune checkpoint inhibitors (ICIs) therapy.
    Keywords:  PD-1/PD-L1 axis; cancer immunotherapy; immune checkpoint inhibitor; sensitization; traditional Chinese medicine
    DOI:  https://doi.org/10.3389/fonc.2023.1168226
  25. Cells. 2023 May 17. pii: 1406. [Epub ahead of print]12(10):
    The Clinical Significance and Role of CXCL1 Chemokine in Gastrointestinal Cancers.
    Jan Korbecki, Mateusz Bosiacki, Katarzyna Barczak, Ryta Łagocka, Dariusz Chlubek, Irena Baranowska-Bosiacka.
      One area of cancer research is the interaction between cancer cells and immune cells, in which chemokines play a vital role. Despite this, a comprehensive summary of the involvement of C-X-C motif ligand 1 (CXCL1) chemokine (also known as growth-regulated gene-α (GRO-α), melanoma growth-stimulatory activity (MGSA)) in cancer processes is lacking. To address this gap, this review provides a detailed analysis of CXCL1's role in gastrointestinal cancers, including head and neck cancer, esophageal cancer, gastric cancer, liver cancer (hepatocellular carcinoma (HCC)), cholangiocarcinoma, pancreatic cancer (pancreatic ductal adenocarcinoma), and colorectal cancer (colon cancer and rectal cancer). This paper presents the impact of CXCL1 on various molecular cancer processes, such as cancer cell proliferation, migration, and invasion, lymph node metastasis, angiogenesis, recruitment to the tumor microenvironment, and its effect on immune system cells, such as tumor-associated neutrophils (TAN), regulatory T (Treg) cells, myeloid-derived suppressor cells (MDSCs), and macrophages. Furthermore, this review discusses the association of CXCL1 with clinical aspects of gastrointestinal cancers, including its correlation with tumor size, cancer grade, tumor-node-metastasis (TNM) stage, and patient prognosis. This paper concludes by exploring CXCL1's potential as a therapeutic target in anticancer therapy.
    Keywords:  CXCL1; GRO-α; MGSA; chemokine; colon cancer; cytokine; hepatocellular carcinoma (HCC); pancreatic ductal adenocarcinoma (PDAC); tumor
    DOI:  https://doi.org/10.3390/cells12101406
  26. Drug Resist Updat. 2023 Jun 28. pii: S1368-7646(23)00071-7. [Epub ahead of print]70 100988
    Purinergic signalling in cancer therapeutic resistance: From mechanisms to targeting strategies.
    Wenhui Jia, Zhao Huang, Li Zhou, Yih-Cherng Liou, Francesco Di Virgilio, Henning Ulrich, Peter Illes, Wei Zhang, Canhua Huang, Yong Tang.
      Purinergic signalling, consisting of extracellular purines and purinergic receptors, modulates cell proliferation, invasion and immunological reaction during cancer progression. Here, we focus on current evidence that suggests the crucial role of purinergic signalling in mediating cancer therapeutic resistance, the major obstacle in cancer treatment. Mechanistically, purinergic signalling can modulate the tumor microenvironment (TME), epithelial-mesenchymal transition (EMT) and anti-tumor immunity, thus affecting drug sensitivity of tumor cells. Currently, some agents attempting to target purinergic signalling either in tumor cells or in tumor-associated immune cells are under preclinical or clinical investigation. Moreover, nano-based delivery technologies significantly improve the efficacy of agents targeting purinergic signalling. In this review article, we summarize the mechanisms of purinergic signalling in promoting cancer therapeutic resistance and discuss the potentials and challenges of targeting purinergic signalling in future cancer treatment.
    Keywords:  Cancer; Purinergic signalling; Targeted therapy; Therapeutic resistance
    DOI:  https://doi.org/10.1016/j.drup.2023.100988
  27. Cell Death Dis. 2023 Jul 04. 14(7): 395
    Stanniocalcin 1 promotes lung metastasis of breast cancer by enhancing EGFR-ERK-S100A4 signaling.
    Anfei Liu, Yunting Li, Sitong Lu, Chunqing Cai, Fei Zou, Xiaojing Meng.
      Lung metastasis is the leading cause of breast cancer-related death. The tumor microenvironment contributes to the metastatic colonization of tumor cells in the lungs. Tumor secretory factors are important mediators for the adaptation of cancer cells to foreign microenvironments. Here, we report that tumor-secreted stanniocalcin 1 (STC1) promotes the pulmonary metastasis of breast cancer by enhancing the invasiveness of tumor cells and promoting angiogenesis and lung fibroblast activation in the metastatic microenvironment. The results show that STC1 modifies the metastatic microenvironment through its autocrine action on breast cancer cells. Specifically, STC1 upregulates the expression of S100 calcium-binding protein A4 (S100A4) by facilitating the phosphorylation of EGFR and ERK signaling in breast cancer cells. S100A4 mediates the effect of STC1 on angiogenesis and lung fibroblasts. Importantly, S100A4 knockdown diminishes STC1-induced lung metastasis of breast cancer. Moreover, activated JNK signaling upregulates STC1 expression in breast cancer cells with lung-tropism. Overall, our findings reveal that STC1 plays important role in breast cancer lung metastasis.
    DOI:  https://doi.org/10.1038/s41419-023-05911-z
  28. Small. 2023 Jul 07. e2303438
    Nonferrous Ferroptosis Inducer Manganese Molybdate Nanoparticles to Enhance Tumor Immunotherapy.
    Huali Lei, Quguang Li, Zifan Pei, Lin Liu, Nailin Yang, Liang Cheng.
      Tumor immunotherapy is an important tool in oncology treatment. However, only a small percentage of patients have an effective immune response to tumor immunotherapy due to the poor infiltration of pro-inflammatory immune cells in immune "cold" tumors and an immunosuppressive network in the tumor microenvironment (TME). Ferroptosis has been widely used as a novel strategy to enhance tumor immunotherapy. Herein, manganese molybdate nanoparticles (MnMoOx NPs) depleted the highly expressed glutathione (GSH) in tumors and inhibited glutathione peroxidase 4 (GPX4) expression, thus triggering ferroptosis, inducing immune cell death (ICD), further releasing damage-associated molecular patterns (DAMPs), and enhancing tumor immunotherapy. Furthermore, MnMoOx NPs can efficiently suppress tumors, promote the maturation of dendritic cells (DCs), infiltrate T cells, and reverse the immunosuppressive microenvironment, making the tumor an immune "hot" tumor. Combination with an immune checkpoint inhibitor (ICI) (α-PD-L1) further enhanced the anti-tumor effect and inhibited metastases as well. The work provides a new idea for the development of nonferrous inducers of ferroptosis to enhance cancer immunotherapy.
    Keywords:  ferroptosis; immune cell death; immunotherapy; manganese molybdate nanoparticles; tumor microenvironment
    DOI:  https://doi.org/10.1002/smll.202303438
  29. Methods Mol Biol. 2023 ;2684 167-175
    Tissue Slice Culture and Analysis of Tumor-Associated Hyaluronan in Urothelial Carcinoma.
    William Donelan, Paul L Crispen, Sergei Kusmartsev.
      Hyaluronan is a major component of the extracellular matrix in both normal and tumor tissue. Many solid cancers, including bladder cancer, are characterized by deregulated hyaluronan metabolism. It is postulated that the deregulated metabolism in cancer tissue is characterized by elevated hyaluronan synthesis and degradation. This results in the accumulation of small hyaluronan fragments in the tumor microenvironment which promotes cancer-related inflammation, stimulates tumor cell proliferation and angiogenesis, and contributes to immune-associated immune suppression. For a better understanding of the complex mechanisms of hyaluronan metabolism in cancer, it has been proposed to use precision-cut tissue slice cultures prepared using freshly excised cancer tissue. Here we describe the protocol for establishing tissue slice cultures and analysis of tumor-associated hyaluronan in human urothelial carcinoma.
    Keywords:  Bladder cancer; Electrophoresis; Hyaluronan; Hyaluronan degradation; Imaging; Tissue slice cultures; Urothelial carcinoma
    DOI:  https://doi.org/10.1007/978-1-0716-3291-8_10
  30. Front Oncol. 2023 ;13 1211456
    Editorial: Hallmark of cancer: avoiding immune suppression.
    Faris Q B Alenzi, Benedetta Apollonio, Liusheng Peng, Elias J Sayour, Michal Sheffer.
      
    Keywords:  cancer immunotherapy; immunosuppression; metabolomics; prediction; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2023.1211456
  31. J Nanobiotechnology. 2023 Jul 08. 21(1): 214
    CAFs targeted ultrasound-responsive nanodroplets loaded V9302 and GLULsiRNA to inhibit melanoma growth via glutamine metabolic reprogramming and tumor microenvironment remodeling.
    Chen Ai, Xiao Sun, Shan Xiao, Lu Guo, Mengmeng Shang, Dandan Shi, Dong Meng, Yading Zhao, Xiaoxuan Wang, Jie Li.
      Despite rapid advances in metabolic therapies over the past decade, their efficacy in melanoma has been modest, largely due to the interaction between cancer-associated fibroblasts (CAFs) and cancer cells to promote cancer growth. Altering the tumor microenvironment (TME) is challenging and elusive. CAFs is critical for glutamine deprivation survival in melanoma. In this research, we assembled a CAFs-targeted, controlled-release nanodroplets for the combined delivery of the amino acid transporter ASCT2 (SLC1A5) inhibitor V9302 and GLULsiRNA (siGLUL). The application of ultrasound-targeted microbubble disruption (UTMD) allows for rapid release of V9302 and siGLUL, jointly breaking the glutamine metabolism interaction between CAFs and cancer cells on one hand, on the other hand, blocking activated CAFs and reducing the expression of extracellular matrix (ECM) to facilitate drug penetration. In addition, ultrasound stimulation made siGLUL more accessible to tumor cells and CAFs, downregulating GLUL expression in both cell types. FH-V9302-siGLUL-NDs also serve as contrast-enhanced ultrasound imaging agents for tumor imaging. Our study developed and reported FH-NDs as nanocarriers for V9302 and siGLUL, demonstrating that FH-V9302-siGLUL-NDs have potential bright future applications for integrated diagnostic therapy. Graphical Abstract.
    Keywords:  Cancer-associated fibroblasts (CAFs); Glutamine metabolism; Metabolic reprogramming; Tumor microenvironment (TME); Ultrasound
    DOI:  https://doi.org/10.1186/s12951-023-01979-z
  32. Exp Mol Med. 2023 Jul 03.
    Cancer-associated fibroblasts: from basic science to anticancer therapy.
    Dakai Yang, Jing Liu, Hui Qian, Qin Zhuang.
      Cancer-associated fibroblasts (CAFs), as a central component of the tumor microenvironment in primary and metastatic tumors, profoundly influence the behavior of cancer cells and are involved in cancer progression through extensive interactions with cancer cells and other stromal cells. Furthermore, the innate versatility and plasticity of CAFs allow their education by cancer cells, resulting in dynamic alterations in stromal fibroblast populations in a context-dependent manner, which highlights the importance of precise assessment of CAF phenotypical and functional heterogeneity. In this review, we summarize the proposed origins and heterogeneity of CAFs as well as the molecular mechanisms regulating the diversity of CAF subpopulations. We also discuss current strategies to selectively target tumor-promoting CAFs, providing insights and perspectives for future research and clinical studies involving stromal targeting.
    DOI:  https://doi.org/10.1038/s12276-023-01013-0
  33. J Transl Med. 2023 Jul 07. 21(1): 449
    Harnessing the potential of CAR-T cell therapy: progress, challenges, and future directions in hematological and solid tumor treatments.
    Gunjan Dagar, Ashna Gupta, Tariq Masoodi, Sabah Nisar, Maysolun Merhi, Sheema Hashem, Ravi Chauhan, Manisha Dagar, Sameer Mirza, Puneet Bagga, Rakesh Kumar, Ammira S Al-Shabeeb Akil, Muzafar A Macha, Mohammad Haris, Shahab Uddin, Mayank Singh, Ajaz A Bhat.
      Traditional cancer treatments use nonspecific drugs and monoclonal antibodies to target tumor cells. Chimeric antigen receptor (CAR)-T cell therapy, however, leverages the immune system's T-cells to recognize and attack tumor cells. T-cells are isolated from patients and modified to target tumor-associated antigens. CAR-T therapy has achieved FDA approval for treating blood cancers like B-cell acute lymphoblastic leukemia, large B-cell lymphoma, and multiple myeloma by targeting CD-19 and B-cell maturation antigens. Bi-specific chimeric antigen receptors may contribute to mitigating tumor antigen escape, but their efficacy could be limited in cases where certain tumor cells do not express the targeted antigens. Despite success in blood cancers, CAR-T technology faces challenges in solid tumors, including lack of reliable tumor-associated antigens, hypoxic cores, immunosuppressive tumor environments, enhanced reactive oxygen species, and decreased T-cell infiltration. To overcome these challenges, current research aims to identify reliable tumor-associated antigens and develop cost-effective, tumor microenvironment-specific CAR-T cells. This review covers the evolution of CAR-T therapy against various tumors, including hematological and solid tumors, highlights challenges faced by CAR-T cell therapy, and suggests strategies to overcome these obstacles, such as utilizing single-cell RNA sequencing and artificial intelligence to optimize clinical-grade CAR-T cells.
    Keywords:  Antigen escape; CAR-T cell therapy; Cytokine release syndrome; Hematological malignancy; Immunotherapy; Solid tumor; Tumor antigens
    DOI:  https://doi.org/10.1186/s12967-023-04292-3
  34. Biochem Biophys Res Commun. 2023 Jun 16. pii: S0006-291X(23)00799-4. [Epub ahead of print]672 201-208
    Metformin ameliorates BMP2 induced adipocyte-like property in breast cancer cells.
    Sneha Soni, Pooja Yadav, Chandi C Mandal.
      Neighboring adipocytes of tumor cells/cancer associated adipocytes supply many factors and fatty acids as fuel to cancer cells for inducing cancer progression and development. Epithelial breast cancer cells also differentiate into several cell types to meet various demands. This study reports that breast cancer cells exhibit inherent adipocyte-like property which is further enhanced in presence of BMP2. Antidiabetic metformin inhibits BMP2 induced adipocyte-like potential in breast cancer cells. Interestingly, breast cancer cells not only show lipid accumulation but also have ability to release lipid content. Thus, this study centers around the presence of the adipocyte cell-like property in breast cancer cells, the significance of BMP2 and metformin that may be explored in designing therapeutics against breast cancer.
    Keywords:  Adipocyte; BMP2; Breast cancer cells; Lipids; Metformin
    DOI:  https://doi.org/10.1016/j.bbrc.2023.06.044
  35. Epigenetics Chromatin. 2023 Jul 06. 16(1): 29
    Etiology of super-enhancer reprogramming and activation in cancer.
    Royce W Zhou, Ramon E Parsons.
      Super-enhancers are large, densely concentrated swaths of enhancers that regulate genes critical for cell identity. Tumorigenesis is accompanied by changes in the super-enhancer landscape. These aberrant super-enhancers commonly form to activate proto-oncogenes, or other genes upon which cancer cells depend, that initiate tumorigenesis, promote tumor proliferation, and increase the fitness of cancer cells to survive in the tumor microenvironment. These include well-recognized master regulators of proliferation in the setting of cancer, such as the transcription factor MYC which is under the control of numerous super-enhancers gained in cancer compared to normal tissues. This Review will cover the expanding cell-intrinsic and cell-extrinsic etiology of these super-enhancer changes in cancer, including somatic mutations, copy number variation, fusion events, extrachromosomal DNA, and 3D chromatin architecture, as well as those activated by inflammation, extra-cellular signaling, and the tumor microenvironment.
    Keywords:  Cancer; Enhancers; Extrachromosomal DNA; Inflammation; Insulators; Non-coding mutations; Phase separation; Super-enhancers; Therapeutic resistance; Topologically associated domain; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13072-023-00502-w
  36. bioRxiv. 2023 Jun 14. pii: 2023.06.14.545005. [Epub ahead of print]
    Hyperglycosylation of prosaposin in tumor DCs promotes immune escape in cancer.
    Pankaj Sharma, Xiaolong Zhang, Kevin Ly, Ji Hyung Kim, Qi Wan, Jessica Kim, Mumeng Lou, Lisa Kain, Luc Teyton, Florian Winau.
      Tumors develop strategies to evade immunity by suppressing antigen presentation. Here, we show that prosaposin drives CD8 T cell-mediated tumor immunity and that its hyperglycosylation in tumor DCs leads to cancer immune escape. We found that lysosomal prosaposin and its single saposin cognates mediated disintegration of tumor cell-derived apoptotic bodies to facilitate presentation of membrane-associated antigen and T cell activation. In the tumor microenvironment, TGF-β induced hyperglycosylation of prosaposin and its subsequent secretion, which ultimately caused depletion of lysosomal saposins. In melanoma patients, we found similar prosaposin hyperglycosylation in tumor-associated DCs, and reconstitution with prosaposin rescued activation of tumor-infiltrating T cells. Targeting tumor DCs with recombinant prosaposin triggered cancer protection and enhanced immune checkpoint therapy. Our studies demonstrate a critical function of prosaposin in tumor immunity and escape and introduce a novel principle of prosaposin-based cancer immunotherapy.
    One Sentence Summary: Prosaposin facilitates antigen cross-presentation and tumor immunity and its hyperglycosylation leads to immune evasion.
    DOI:  https://doi.org/10.1101/2023.06.14.545005
  37. Cancer Res. 2023 Jul 05. pii: CAN-23-1948. [Epub ahead of print]
    Uncovering the Role of CD4+ CAR T Cells in Cancer Immunotherapy.
    Darya Alizadeh, Dongrui Wang, Christine E Brown.
      Chimeric antigen receptor (CAR) T cell therapy has transformed clinical care against blood malignancies and is seeing encouraging progress against solid tumors. While scientific advancement has been rapid, our mechanistic understanding of intrinsic features of CAR-engineered T cells is still evolving. CAR products typically consist of CD4+ and CD8+ T cell subsets at variable ratios, yet a clear understanding of how each subset contributes together and independently to therapeutic response is lacking. CD8+ CAR T cells are well-characterized for their perforin-dependent killing effects; however, the role of CD4+ CAR T cells as 'helpers' versus 'killers' has been variable across models and warrants more in-depth investigation. A recent study by Boulch and colleagues published in Nature Cancer demonstrates that CD4+ CAR T cells, alone, can exert potent antitumor activity through a mechanism involving IFNγ. CD4+ CAR T cell production of IFNγ creates a cytokine field that can act at a distance to kill both antigen positive and negative tumor cells that are sensitive to the pro-apoptotic effects of IFNγ. These new findings reveal important insights for the antitumor effects mediated by CD4+ CAR T cells, which could have significant clinical implications.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-1948
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