bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–11–03
twenty papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Insights into CSF-1R Expression in the Tumor Microenvironment.
  2. Immune therapeutic strategies for the senescent tumor microenvironment.
  3. Metabolic gatekeepers: harnessing tumor-derived metabolites to optimize T cell-based immunotherapy efficacy in the tumor microenvironment.
  4. Targeting metabolic pathway enhance CAR-T potency for solid tumor.
  5. CD84 as a therapeutic target for breaking immune tolerance in triple-negative breast cancer.
  6. Sugar symphony: glycosylation in cancer metabolism and stemness.
  7. An insight into the role of innate immune cells in breast tumor microenvironment.
  8. Alleviating tumor hypoxia and immunosuppression via sononeoperfusion: A new Ally for potentiating anti-PD-L1 blockade of solid tumor.
  9. Impact of mitochondrial dysfunction on the antitumor effects of immune cells.
  10. The influence of biophysical niche on tumor-associated macrophages in liver cancer.
  11. Systemic and local chronic inflammation and hormone disposition promote a tumor-permissive environment for breast cancer in older women.
  12. Research progress of tumor-associated macrophages in immune checkpoint inhibitor tolerance in colorectal cancer.
  13. Decoding secret role of mesenchymal stem cells in regulating cancer stem cells and drug resistance.
  14. From darkness to light: Targeting CAFs as a new potential strategy for cancer treatment.
  15. How lactate affects immune strategies in lymphoma.
  16. Immunoglobulin-binding protein and Toll-like receptors in immune landscape of breast cancer.
  17. Emerging Role of the p53 Pathway in Modulating Natural Killer Cell Mediated Immunity.
  18. The Influence of Microbiota on Breast Cancer: A Review.
  19. [PD-L1-Expressing Cancer-Associated Fibroblasts Have the Potential of a Biomarker for Immune Checkpoint Inhibitors].
  20. Anti-PD-L1 chimeric antigen receptor natural killer cell: Characterization and functional analysis.
  1. Biomedicines. 2024 Oct 18. pii: 2381. [Epub ahead of print]12(10):
    Insights into CSF-1R Expression in the Tumor Microenvironment.
    Caterina Tomassetti, Gaia Insinga, Francesca Gimigliano, Andrea Morrione, Antonio Giordano, Emanuele Giurisato.
      The colony-stimulating factor 1 receptor (CSF-1R) plays a pivotal role in orchestrating cellular interactions within the tumor microenvironment (TME). Although the CSF-1R has been extensively studied in myeloid cells, the expression of this receptor and its emerging role in other cell types in the TME need to be further analyzed. This review explores the multifaceted functions of the CSF-1R across various TME cellular populations, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), cancer-associated fibroblasts (CAFs), endothelial cells (ECs), and cancer stem cells (CSCs). The activation of the CSF-1R by its ligands, colony-stimulating factor 1 (CSF-1) and Interleukin-34 (IL-34), regulates TAM polarization towards an immunosuppressive M2 phenotype, promoting tumor progression and immune evasion. Similarly, CSF-1R signaling influences MDSCs to exert immunosuppressive functions, hindering anti-tumor immunity. In DCs, the CSF-1R alters antigen-presenting capabilities, compromising immune surveillance against cancer cells. CSF-1R expression in CAFs and ECs regulates immune modulation, angiogenesis, and immune cell trafficking within the TME, fostering a pro-tumorigenic milieu. Notably, the CSF-1R in CSCs contributes to tumor aggressiveness and therapeutic resistance through interactions with TAMs and the modulation of stemness features. Understanding the diverse roles of the CSF-1R in the TME underscores its potential as a therapeutic target for cancer treatment, aiming at disrupting pro-tumorigenic cellular crosstalk and enhancing anti-tumor immune responses.
    Keywords:  CAFs; CSF-1R; ECs; MDSCs; TAMs; cancer stem cells; tumor microenvironment
    DOI:  https://doi.org/10.3390/biomedicines12102381
  2. Br J Cancer. 2024 Oct 28.
    Immune therapeutic strategies for the senescent tumor microenvironment.
    Tadahito Yasuda, Y Alan Wang.
      Senescent cells can either to promote immunosuppressive tumor microenvironment or facilitate immune surveillance. Despite the revolutionary impact of cancer immunotherapy, durable responses in solid tumors, particularly in advanced stages, remain limited. Recent studies have shed light on the influence of senescent status within the tumor microenvironment (TME) on therapy resistance and major efforts are needed to overcome these challenges. This review summarizes recent advancements in targeting cellular senescence, with a particular focus on immunomodulatory approaches on the hallmarks of cellular senescence.
    DOI:  https://doi.org/10.1038/s41416-024-02865-7
  3. Cell Death Dis. 2024 Oct 26. 15(10): 775
    Metabolic gatekeepers: harnessing tumor-derived metabolites to optimize T cell-based immunotherapy efficacy in the tumor microenvironment.
    Yucheng Zheng, Rongwei Xu, Xu Chen, Ye Lu, Jiarong Zheng, Yunfan Lin, Pei Lin, Xinyuan Zhao, Li Cui.
      The tumor microenvironment (TME) orchestrates a complex interplay between tumor cells and immune cells, crucially modulating the immune response. This review delves into the pivotal role of metabolic reprogramming in the TME, highlighting how tumor-derived metabolites influence T lymphocyte functionality and the efficacy of cancer immunotherapies. Focusing on the diverse roles of these metabolites, we examine how lactate, lipids, amino acids, and other biochemical signals act not only as metabolic byproducts but as regulatory agents that can suppress or potentiate T cell-mediated immunity. By integrating recent findings, we underscore the dual impact of these metabolites on enhancing tumor progression and inhibiting immune surveillance. Furthermore, we propose innovative therapeutic strategies that target metabolic pathways to restore immune function within the TME. The insights provided in this review pave the way for the development of metabolic interventions aimed at enhancing the success of immunotherapies in oncology, offering new hope for precision medicine in the treatment of cancer.
    DOI:  https://doi.org/10.1038/s41419-024-07122-6
  4. Int Immunopharmacol. 2024 Oct 24. pii: S1567-5769(24)01934-9. [Epub ahead of print]143(Pt 2): 113412
    Targeting metabolic pathway enhance CAR-T potency for solid tumor.
    Wenying Li, Jiannan Chen, Zhigang Guo.
      Chimeric antigen receptor (CAR) T cells have great potential in cancer therapy, particularly in treating hematologic malignancies. However, their efficacy in solid tumors remains limited, with a significant proportion of patients failing to achieve long-term complete remission. One major challenge is the premature exhaustion of CAR-T cells, often due to insufficient metabolic energy. The survival, function and metabolic adaptation of CAR-T cells are key determinants of their therapeutic efficacy. We explore how targeting metabolic pathways in the tumor microenvironment can enhance CAR-T cell therapy by addressing metabolic competition and immunosuppression that impair CAR-T cell function. Tumors undergo metabolically reprogrammed to meet their rapid proliferation, thereby modulating metabolic pathways in immune cells to promote immunosuppression. The distinct metabolic requirements of tumors and T cells create a competitive environment, affecting the efficacy of CAR-T cell therapy. Recent research on glucose, lipid and amino acid metabolism, along with the interactions between tumor and immune cell metabolism, has revealed that targeting these metabolic processes can enhance antitumor immune responses. Combining metabolic interventions with existing antitumor therapies can fulfill the metabolic demands of immune cells, providing new ideas for tumor immunometabolic therapies. This review discusses the latest advances in the immunometabolic mechanisms underlying tumor immunosuppression, their implications for immunotherapy, and summarizes potential metabolic targets to improve the efficacy of CAR-T therapy.
    Keywords:  CAR-T cell therapy; Immunotherapy; Metabolism reprogramming; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2024.113412
  5. Cell Rep. 2024 Oct 27. pii: S2211-1247(24)01271-3. [Epub ahead of print]43(11): 114920
    CD84 as a therapeutic target for breaking immune tolerance in triple-negative breast cancer.
    Stav Rabani, Emine Gulsen Gunes, Martin Gunes, Bianca Pellegrino, Bar Lampert, Keren David, Raju Pillai, Aimin Li, Shirly Becker-Herman, Steven T Rosen, Idit Shachar.
      Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. The tumor microenvironment (TME) plays a major regulatory role in TNBC progression and is highly infiltrated by suppressive immune cells that reduce anti-tumor immune activity. Although regulatory B cells (Bregs) are a key TME component, knowledge of their function in TNBC is limited. CD84 is a homophilic adhesion molecule that promotes the survival of blood tumors. In the current study, we followed the role of CD84 in the regulation of the TME in TNBC. We demonstrate that CD84 induces a cascade in Bregs that involves the β-catenin and Tcf4 pathway, which induces the transcription of interleukin-10 by binding to its promoter and the promoter of its regulator, AhR. This leads to the expansion of Bregs, which in turn control the activity of other immune cells and immune suppression. Accordingly, we suggest CD84 as a therapeutic target for breaking immune tolerance in TNBC.
    Keywords:  Bregs; CD84; CP: Cancer; CP: Immunology; IL-10; SLAM; SLAMF5; TNBC; Tcf4; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2024.114920
  6. Trends Cell Biol. 2024 Oct 26. pii: S0962-8924(24)00206-X. [Epub ahead of print]
    Sugar symphony: glycosylation in cancer metabolism and stemness.
    Venkatesh Varadharaj, Wyatt Petersen, Surinder K Batra, Moorthy P Ponnusamy.
      Glycosylation is a complex co-translational and post-translational modification (PTM) in eukaryotes that utilizes glycosyltransferases to generate a vast array of glycoconjugate structures. Recent studies have highlighted the role of glycans in regulating essential molecular, cellular, tissue, organ, and systemic biological processes with significant implications for human diseases, particularly cancer. The metabolic reliance of cancer, spanning tumor initiation, disease progression, and resistance to therapy, necessitates a range of uniquely altered cellular metabolic pathways. In addition, the intricate interplay between cell-intrinsic and -extrinsic mechanisms is exemplified by the communication between cancer cells, cancer stem cells (CSCs), cancer-associated fibroblasts (CAFs), and immune cells within the tumor microenvironment (TME). In this review article, we explore how differential glycosylation in cancer influences the metabolism and stemness features alongside new avenues in glycobiology.
    Keywords:  glycoconjugate; glycosyltransferase; metabolism; stemness
    DOI:  https://doi.org/10.1016/j.tcb.2024.09.006
  7. Breast Cancer. 2024 Oct 26.
    An insight into the role of innate immune cells in breast tumor microenvironment.
    Sandini Garg, Garima Rai, Sakshi Singh, Pammi Gauba, Javed Ali, Shweta Dang.
      The immune background of breast cancer is highly heterogeneous and the immune system of the human body plays a dual role by both promoting and suppressing its progression. Innate immune cells are the first line of defense in the immune system and impart protection by identifying and interacting with foreign pathogens and cancer cells. Different innate immune cells like natural killer cells, macrophages, dendritic cells, and myeloid suppressor cells take part in hosting the cancer cells. Autophagy is another key component inside the tumor microenvironment and is linked to the disintegration and recycling of cellular components. Within the tumor microenvironment autophagy is involved with Pattern Recognition Receptors and inflammation. Various clinical studies have shown prominent results where innate immune cells and autophagy in combination are used for pathogen as well as cancer cell clearance. However, it is necessary to comprehend the complex tumor microenvironment so that different therapeutic approaches can be developed to enhance the suppressive actions of the cells toward breast cancer cells. In this review article, the complex interaction between immune cells and breast cancer cells and their role in developing effective immunotherapies to improve patient outcomes are discussed in detail.
    Keywords:  Breast cancer; Immunotherapies; Innate immune cells; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12282-024-01645-8
  8. Ultrason Sonochem. 2024 Oct 22. pii: S1350-4177(24)00363-8. [Epub ahead of print] 107115
    Alleviating tumor hypoxia and immunosuppression via sononeoperfusion: A new Ally for potentiating anti-PD-L1 blockade of solid tumor.
    Guoliang Yang, Hui Li, Jiabei Yin, Lei Yao, Jun Yang, Jiawei Tang, You Wu, Meng Zhou, TingTing Luo, Yi Zhang, Jing Zhang, Xuezhi Yang, XiaoXiao Dong, Zheng Liu, Ningshan Li.
      The hypoxic and immunosuppressive tumor microenvironment (TME) remains a major obstacle to impede cancer immunotherapy. Here, we found that sononeoperfusion-a new effect of tumor perfusion enhancement induced by low mechanical index ultrasound stimulated microbubble cavitation (USMC)-ameliorated tumor tissue oxygenation and induced tumor vascular normalization (TVN). This TVN might be associated with the down-regulation of hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF) within tumors. Moreover, the sononeoperfusion effect reduced the accumulation of immunosuppressive cells, such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and M2-like tumor-associated macrophages (M2-TAMs), and decreased the production of immune inhibitory factors like transforming growth factor-β1 (TGF-β1), interleukin 10 (IL-10), chemoattractant chemokines CC-chemokine ligand 22 (CCL22), CCL28, adenosine and lactate within tumors. Notably, flow cytometry analysis revealed that sononeoperfusion not only increased the percentage of tumor infiltrating-CD8+ T cells, but also promoted the generation of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) by these cells. Furthermore, the improved immune TME by sononeoperfusion effect sensitized anti-PD-L1 treatment both in MC38 colon cancer and Lewis lung carcinoma mice, resulting in tumor regression and prolonged survival. Mechanically, the enhanced efficacy of combination therapy was mainly based on promoting the infiltration and function of CD8+ T cells within tumors. Together, sononeoperfusion could ameliorate hypoxia and immunosuppression in the TME, thereby potentiating anti-PD-L1 therapy for solid tumors. This novel method of USMC generating sononeoperfusion effect may provide a new therapeutic modality for facilitating cancer immunotherapy.
    Keywords:  Immunotherapy; Sononeoperfusion; Tumor hypoxia; Tumor microenvironment; Ultrasound cavitation; Vascular normalization
    DOI:  https://doi.org/10.1016/j.ultsonch.2024.107115
  9. Front Immunol. 2024 ;15 1428596
    Impact of mitochondrial dysfunction on the antitumor effects of immune cells.
    Quan Wang, Xiangzhi Yin, Xiaotong Huang, Lu Zhang, Haijun Lu.
      Mitochondrial dysfunction, a hallmark of immune cell failure, affects the antitumor effects of immune cells through metabolic reprogramming, fission, fusion, biogenesis, and immune checkpoint signal transduction of mitochondria. According to researchers, restoring damaged mitochondrial function can enhance the efficacy of immune cells. Nevertheless, the mechanism of mitochondrial dysfunction in immune cells in patients with cancer is unclear. In this review, we recapitulate the impact of mitochondrial dysfunction on the antitumor effects of T cells, natural killer cells, dendritic cells, and tumor-associated macrophage and propose that targeting mitochondria can provide new strategies for antitumor therapy.
    Keywords:  immune cell; immune regulation; immunotherapy; mitochondrial dysfunction; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1428596
  10. Hepatol Commun. 2024 Nov 01. pii: e0569. [Epub ahead of print]8(11):
    The influence of biophysical niche on tumor-associated macrophages in liver cancer.
    Ying Zhang, Ying Rao, Jiahuan Lu, Jiyu Wang, Dai Fei Elmer Ker, Jingying Zhou, Dan Michelle Wang.
      HCC, the most common type of primary liver cancer, is a leading cause of cancer-related mortality worldwide. Although the advancement of immunotherapies by immune checkpoint inhibitors (ICIs) that target programmed cell death 1 or programmed cell death 1-ligand 1 has revolutionized the treatment for HCC, the majority is still not beneficial. Accumulating evidence has pointed out that the potent immunosuppressive tumor microenvironment in HCC poses a great challenge to ICI therapeutic efficacy. As a key component in tumor microenvironment, tumor-associated macrophages (TAMs) play vital roles in HCC development, progression, and ICI low responsiveness. Mechanistically, TAM can promote cancer invasion and metastasis, angiogenesis, epithelial-mesenchymal transition, maintenance of stemness, and most importantly, immunosuppression. Targeting TAMs, therefore, represents an opportunity to enhance the ICI therapeutic efficacy in patients with HCC. While previous research has primarily focused on biochemical cues influencing macrophages, emerging evidence highlights the critical role of biophysical signals, such as substrate stiffness, topography, and external forces. In this review, we summarize the influence of biophysical characteristics within the tumor microenvironment that regulate the phenotype and function of TAMs in HCC pathogenesis and progression. We also explore the possible mechanisms and discuss the potential of manipulating biophysical cues in regulating TAM for HCC therapy. By gaining a deeper understanding of how macrophages sense and respond to mechanical forces, we may potentially usher in a path toward a curative approach for combinatory cancer immunotherapies.
    DOI:  https://doi.org/10.1097/HC9.0000000000000569
  11. bioRxiv. 2024 Oct 21. pii: 2024.10.18.616978. [Epub ahead of print]
    Systemic and local chronic inflammation and hormone disposition promote a tumor-permissive environment for breast cancer in older women.
    Neil Carleton, Sanghoon Lee, Ruxuan Li, Jian Zou, Daniel D Brown, Jagmohan Hooda, Alexander Chang, Rahul Kumar, Linda R Klei, Lora H Rigatti, Joseph Newsome, Dixcy Jaba Sheeba John Mary, Jennifer M Atkinson, Raymond E West, Thomas D Nolin, Patrick J Oberly, Ziyu Huang, Donald Poirier, Emilia J Diego, Peter C Lucas, George Tseng, Michael T Lotze, Priscilla F McAuliffe, Ioannis K Zervantonakis, Steffi Oesterreich, Adrian V Lee.
      Estrogen receptor positive (ER+) breast cancer is the most common subtype of breast cancer and is an age-related disease. The peak incidence of diagnosis occurs around age 70, even though these post-menopausal patients have low circulating levels of estradiol (E2). Despite the hormone sensitivity of age-related tumors, we have a limited understanding of the interplay between systemic and local hormones, chronic inflammation, and immune changes that contribute to the growth and development of these tumors. Here, we show that aged F344 rats treated with the dimethylbenz(a)anthracene / medroxyprogestrone acetate (DMBA/MPA) carcinogen develop more tumors at faster rates than their younger counterparts, suggesting that the aged environment promotes tumor initiation and impacts growth. Single-nuclei RNA-seq (snRNA-seq) of the tumors showed broad local immune dysfunction that was associated with circulating chronic inflammation. Across a broad cohort of specimens from patients with ER+ breast cancer and age-matched donors of normal breast tissue, we observe that even with an estrone (E1)-predominant estrogen disposition in the systemic circulation, tumors in older patients increase HSD17B7 expression to convert E1 to E2 in the tumor microenvironment (TME) and have local E2 levels similar to pre-menopausal patients. Concurrently, trackable increases in several chemokines, defined most notably by CCL2, promote a chronically inflamed but immune dysfunctional TME. This unique milieu in the aged TME, characterized by high local E2 and chemokine-enriched chronic inflammation, promotes both accumulation of tumor-associated macrophages (TAMs), which serve as signaling hubs, as well as polarization of TAMs towards a CD206+/PD-L1+, immunosuppressive phenotype. Pharmacologic targeting of estrogen signaling (either by HSD17B7 inhibition or with fulvestrant) and chemokine inflammation both decrease local E2 and prevent macrophage polarization. Overall, these findings suggest that chronic inflammation and hormonal disposition are critical contributors to the age-related nature of ER+ breast cancer development and growth and offer potential therapeutic insight to treat these patients.
    Translational Summary: We uncover the unique underpinnings establishing how the systemic host environment contributes to the aged breast tumor microenvironment, characterized by high local estradiol and chronic inflammation with immune dysregulation, and show that targeting avenues of estrogen conversion and chronic inflammation work to restore anti-tumor immunity.
    DOI:  https://doi.org/10.1101/2024.10.18.616978
  12. World J Gastrointest Oncol. 2024 Oct 15. 16(10): 4064-4079
    Research progress of tumor-associated macrophages in immune checkpoint inhibitor tolerance in colorectal cancer.
    Qi Fan, Zheng-Wei Fu, Ming Xu, Feng Lv, Jia-Song Shi, Qi-Qi Zeng, De-Hai Xiong.
      The relevant mechanism of tumor-associated macrophages (TAMs) in the treatment of colorectal cancer patients with immune checkpoint inhibitors (ICIs) is discussed, and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies. As a class of drugs widely used in clinical tumor immunotherapy, ICIs can act on regulatory molecules on cells that play an inhibitory role-immune checkpoints-and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system. The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly. The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs. ICIs can regulate the phenotypic function of TAMs, and TAMs can also affect the tolerance of colorectal cancer to ICI therapy. TAMs play an important role in ICI resistance, and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.
    Keywords:  Colorectal cancer; Immune checkpoint inhibitor resistance; Review; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.4251/wjgo.v16.i10.4064
  13. Biochim Biophys Acta Rev Cancer. 2024 Oct 29. pii: S0304-419X(24)00136-7. [Epub ahead of print]1879(6): 189205
    Decoding secret role of mesenchymal stem cells in regulating cancer stem cells and drug resistance.
    Sameer Kumar Panda, Nirmal Robinson, Vincenzo Desiderio.
      Drug resistance caused by the efflux of chemotherapeutic drugs is one of the most challenging obstacles to successful cancer therapy. Several efflux transporters have been identified since the discovery of the P-gp/ABCB1 transporter in 1976. Over the last four decades, researchers have focused on developing efflux transporter inhibitors to overcome drug resistance. However, even with the third-generation inhibitors available, we are still far from effectively inhibiting the efflux transporters. Additionally, Cancer stem cells (CSCs) pose another significant challenge, contributing to cancer recurrence even after successful treatment. The ability of CSCs to enter dormancy and evade detection makes them almost invulnerable to chemotherapeutic drug treatment. In this review, we discuss how Mesenchymal stem cells (MSCs), one of the key components of the Tumor Microenvironment (TME), regulate both the CSCs and efflux transporters. We propose a new approach focusing on MSCs, which can be crucial to successfully address CSCs and efflux transporters.
    Keywords:  ATP transporters; Cancer stem cells; Drug efflux; Drug resistance; Mesenchymal stem cells; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2024.189205
  14. Int Immunopharmacol. 2024 Oct 29. pii: S1567-5769(24)02004-6. [Epub ahead of print]143(Pt 2): 113482
    From darkness to light: Targeting CAFs as a new potential strategy for cancer treatment.
    Haixia Tian, Weijing Wang, Shuai Liang, Junli Ding, Dong Hua.
      Cancer-associated fibroblasts (CAFs), which are the most frequent stromal cells in the tumor microenvironment (TME), play a key role in the metastasis of tumor cells. Generally speaking, CAFs in cooperation with tumor cells can secrete various cytokines, proteins, growth factors, and metabolites to promote angiogenesis, mediate immune escape of tumor cells, enhance endothelial-to-mesenchymal transition, stimulate extracellular matrix remodeling, and preserve tumor cell stemness. These activities of CAFs provide a favorable exogenous pathway for tumor progression and metastasis, and a microenvironment that allows rapid growth of tumor cells, which always lead to poor prognosis for patients. More importantly, it seems that targeting CAFs is also a potential precision therapeutic strategy in clinical practice. Hence, this review outlines the origin of CAFs, the relationship between CAFs and cancer metastasis, and targeting CAFs as a potential strategy for cancer patients, which could give some inspirations for cancer treatment in clinic.
    Keywords:  Cancer treatment; Cancer-associated fibroblasts (CAFs); Clinical practice; Metastasis; Targeting CAFs
    DOI:  https://doi.org/10.1016/j.intimp.2024.113482
  15. Front Mol Biosci. 2024 ;11 1480884
    How lactate affects immune strategies in lymphoma.
    Yuehan Zhou, Jinzhan Lou, Yuqin Tian, Jinlei Ding, Xiaobo Wang, Bo Tang.
      Tumor cells undergo metabolic reprogramming through shared pathways, resulting in a hypoxic, acidic, and highly permeable internal tumor microenvironment (TME). Lactate, once only regarded as a waste product of glycolysis, has an inseparable dual role with tumor immunity. It can not only provide a carbon source for immune cells to enhance immunity but also help the immune escape through a variety of ways. Lymphoma also depends on the proliferation signal of TME. This review focuses on the dynamic process of lactate metabolism and immune function changes in lymphoma and aims to comprehensively summarize and explore which genes, transcription factors, and pathways affect the biological changes and functions of immune cells. To deeply understand the complex and multifaceted role of lactate metabolism and immunity in lymphoma, the combination of lactate targeted therapy and classical immunotherapy will be a promising development direction in the future.
    Keywords:  HIF-1α; MTOR signaling; MYC; NF-κB signaling; immune cells; immune checkpoints; lactate; lymphoma
    DOI:  https://doi.org/10.3389/fmolb.2024.1480884
  16. Life Sci. 2024 Oct 29. pii: S0024-3205(24)00786-0. [Epub ahead of print] 123196
    Immunoglobulin-binding protein and Toll-like receptors in immune landscape of breast cancer.
    Priyamvada Bhamidipati, Ganji Purnachandra Nagaraju, RamaRao Malla.
      Breast cancer (BC) is a complex disease exhibiting significant heterogeneity and encompassing various molecular subtypes. Among these, triple-negative breast cancer (TNBC) stands out as one of the most challenging types, characterized by its aggressive nature and poor prognosis. This review embarks on a comprehensive exploration of the immune landscape of BC, with a primary focus on the functional and structural characterization of immunoglobulin-binding protein (BiP) and its pivotal role in regulating the unfolded response (UPR) pathway of proteins. Moreover, we unravel the multifaceted functions of BiP in BC, with a special emphasis on the involvement of cell surface BiP in TNBC metastasis, drug resistance, and its contribution to the formation of the tumor microenvironment (TME). We also provide mechanistic insights into how ER-resident BiP mediates the sensitization of drug-resistant BC to different treatment strategies, thereby offering promising avenues for therapeutic intervention. We also delve into the role of Toll-like receptors (TLRs), shedding light on their diverse expression patterns across BC and their influence on modulating the tumor immune response. Understanding the interplay between BiP, TLRs, and the immune response, especially in TNBC, opens avenues for novel immunotherapies. Future research should focus on developing targeted therapies that activate ER-resident BiP or inhibit cell surface BiP, and modulate TLR signaling. Moreover, exploring BiP as a biomarker for TNBC diagnosis, prognosis, and treatment response will be crucial for personalized medicine.
    Keywords:  Breast cancer; Immune landscape; Immunoglobulin-binding protein; TME; Toll-like receptor
    DOI:  https://doi.org/10.1016/j.lfs.2024.123196
  17. Mol Cancer Ther. 2024 Oct 29.
    Emerging Role of the p53 Pathway in Modulating Natural Killer Cell Mediated Immunity.
    Yu-Chi Chen, Christopher G Bazewicz, Saketh S Dinavahi, Nicholas D Huntington, Todd D Schell, Gavin P Robertson.
      The p53 pathway plays an important role in role in cancer immunity. Mutation or downregulation of the proteins in the p53 pathway are prevalent in many cancers, contributing to tumor progression and immune dysregulation. Recent findings suggest that the activity of p53 within tumor cells, immune cells, and the tumor microenvironment can play an important role modulating natural killer (NK) cell-mediated immunity. Consequently, efforts to restore p53 pathway activity are being actively pursued to modulate this form of immunity. This review focuses on p53 activity regulating the infiltration and the activation of NK cells in the tumor immune microenvironment, which are illustrated in the Graphical Abstract for this review. Furthermore, impact of p53 and its regulation of NK cells on immunogenic cell death within solid tumors and the abscopal effect is reviewed. Finally, future avenues for therapeutically restoring p53 activity to improve NK cell-mediated anti-tumor immunity and optimize the effectiveness of cancer therapies are discussed.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-24-0325
  18. Cancers (Basel). 2024 Oct 13. pii: 3468. [Epub ahead of print]16(20):
    The Influence of Microbiota on Breast Cancer: A Review.
    Cara-Xenia-Rafaela Neagoe, Mihaela Ionică, Octavian Constantin Neagoe, Adrian Pavel Trifa.
      Breast cancer remains one of the leading causes of death among women worldwide, and recent research highlights its growing connection to alterations in the microbiota. This review delves into the intricate relationship between microbiotas and breast cancer, exploring its presence in healthy breast tissue, its changes during cancer progression, and its considerable impact on both the tumor microenvironment (TME) and the tumor immune microenvironment (TIME). We extensively analyze how the microbiota influences cancer growth, invasion, metastasis, resistance to drugs, and the evasion of the immune system, with a special focus on its effects on the TIME. Furthermore, we investigate distinct microbial profiles associated with the four primary molecular subtypes of breast cancer, examining how the microbiota in tumor tissues compares with that in adjacent normal tissues. Emerging studies suggest that microbiotas could serve as valuable diagnostic and prognostic biomarkers, as well as targets for therapy. This review emphasizes the urgent need for further research to improve strategies for breast cancer prevention, diagnosis, and treatment. By offering a detailed examination of the microbiota's critical role in breast cancer, this review aims to foster the development of novel microbiota-based approaches for managing the disease.
    Keywords:  breast cancer; microbial signatures; microbiome; microbiota; tumor immune microenvironment; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers16203468
  19. Gan To Kagaku Ryoho. 2024 Sep;51(9): 865-868
    [PD-L1-Expressing Cancer-Associated Fibroblasts Have the Potential of a Biomarker for Immune Checkpoint Inhibitors].
    Kento Kawasaki, Kazuhiro Noma, Toshiyoshi Fujiwara.
      Programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1)axis is well known as the system resulting in the inhibition of immune responses and promotion of self-tolerance. The clinical indications for immune checkpoint inhibitors( ICIs), including the targeting of PD-1/PD-L1 axis, are dramatically expanding. However, since ICIs have been found to be ineffective or resistant in some types of cancer, the development of more effective combination therapies or predictors and biomarkers of efficacy are expected. On the other hand, we have been focusing on the tumor microenvironment(TME)as a therapeutic target, and have been analyzing the function of cancer-associated fibroblasts(CAFs), which play a central role in TME. Recently, CAFs are known to induce tumors to an immunosuppressive state, suggesting that ICIs may not be effective in such a cancer microenvironment. In this review, we demonstrated the impact of PD-L1 positivity in cancer cells and CAFs by immunohistochemistry for resected specimens. In addition, we evaluated the potential of PD-L1-positve CAFs for therapeutic target and biomarker for ICIs.
  20. APMIS. 2024 Oct 28.
    Anti-PD-L1 chimeric antigen receptor natural killer cell: Characterization and functional analysis.
    Mahsa Yazdanpanah-Samani, Amin Ramezani, Abdolkarim Sheikhi, Zohreh Mostafavi-Pour, Nasrollah Erfani.
      Like their natural counterparts, chimeric antigen receptor-engineered cells are prone to suppression by inhibitory signals, such as PD-L1, expressed by tumors or suppressor cells in the tumor microenvironment. Consequently, they become impaired, resulting in immune cell exhaustion, tumor progression, and resistance to other therapies. In this study, we developed an anti-PD-L1-CAR NK cell with efficient activity and a notable PD-L1-specific response toward tumor cell lines. The degranulation assay demonstrated that CD107a frequencies between the PD-L1med and PD-L1high groups and between Herceptin-treated and non-treated groups were not statistically different. Further investigation into NK cell characterization, considering different markers such as CD57, KIR2D, and CD25, revealed that the majority of the population are activated expanding NK cells. At the same time, immune checkpoint inhibitors, including PD-1, PD-L1, and LAG-3, showed increased levels following activation and expansion. Regarding the efficient functional activity of PD-L1-CAR NK cells and the instinctive receptor balance-based response of NK cells, this observation could point to the inhibition of NK cell overactivation or even higher cytotoxicity and cytokine production rather than exhaustion, especially in the case of healthy NK cells. These findings can contribute to a better understanding of the potential and challenges of using primary NK cells for CAR-NK cell therapy.
    Keywords:  CAR‐NK cell; Cancer immunotherapy; PD‐L1; chimeric antigen receptor; immune checkpoint inhibitors; tumor microenvironment
    DOI:  https://doi.org/10.1111/apm.13471
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