bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023‒10‒08
twenty-one papers selected by
Peio Azcoaga, Biodonostia HRI

  1. Carcinogenesis. 2023 Oct 05. pii: bgad072. [Epub ahead of print]
      The inflammasomes play crucial roles in inflammation and cancer development, while the PD-1/PD-L1 pathway is critical for immune suppression in the tumor microenvironment (TME). Recent research indicates a reciprocal regulatory relationship between inflammasomes and PD-1/PD-L1 signaling in cancer development and PD-1 blockade treatment. By activating in diverse cells in tumor tissues, inflammasome upregulates PD-L1 level in the TME. Moreover, the regulation of PD-1/PD-L1 activity by inflammasome activation involves natural killer (NK) cells, tumor-associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs). Conversely, PD-1 blockade can activate the inflammasome, potentially influencing treatment outcomes. The interplay between inflammasomes and PD-1/PD-L1 has profound and intricate effects on cancer development and treatment. In this review, we discuss the crosstalk between inflammasomes and PD-1/PD-L1 in cancers, exploring their implications for tumorigenesis, metastasis and ICI resistance. The combined therapeutic strategies targeting both inflammasomes and checkpoint molecules hold promising potential as treatments for cancer.
    Keywords:  Inflammasome; PD-1; PD-L1; cancer; immunotherapy
  2. Front Biosci (Landmark Ed). 2023 Sep 15. 28(9): 207
      Tumor-associated macrophages (TAMs) are the most abundant infiltrating immune cells in the tumor microenvironment (TME) and play an important role in tumor progression. Clinically, the increase of TAMs infiltration is linked to poor prognosis of patients with various cancer types. Multiple studies have demonstrated that reducing or reprogramming TAMs can inhibit the occurrence or development of tumors. Therefore, TAMs have been identified as novel targets for the treatment of cancer therapy. In this review, the origin, polarization, roles, and targeting of TAMs in malignancies, are discussed.
    Keywords:  cancer therapy; macrophage roles; macrophage targeting; tumor microenvironment; tumor-associated macrophages
  3. Int J Biol Sci. 2023 ;19(15): 4915-4930
      Breast cancer is the most common cancer affecting women worldwide. Investigating metabolism in breast cancer may accelerate the exploitation of new therapeutic options for immunotherapies. Metabolic reprogramming can confer breast cancer cells (BCCs) with a survival advantage in the tumor microenvironment (TME) and metabolic alterations in breast cancer, and the corresponding metabolic byproducts can affect the function of tumor-associated macrophages (TAMs). Additionally, TAMs undergo metabolic reprogramming in response to signals present in the TME, which can affect their function and breast cancer progression. Here, we review the metabolic crosstalk between BCCs and TAMs in terms of glucose, lipids, amino acids, iron, and adenosine metabolism. Summaries of inhibitors that target metabolism-related processes in BCCs or TAMs within breast cancer have also served as valuable inspiration for novel therapeutic approaches in the fight against this disease. This review provides new perspectives on targeted anticancer therapies for breast cancer that combine immunity with metabolism.
    Keywords:  breast cancer; crosstalk; metabolism; targeted therapy; tumor-associated macrophages
  4. Cancer Immunol Immunother. 2023 Oct 05.
      Macrophages are important precursor cell types of the innate immune system and bridge adaptive immune responses through the antigen presentation system. Meanwhile, macrophages constitute substantial portion of the stromal cells in the tumor microenvironment (TME) (referred to as tumor-associated macrophages, or TAMs) and exhibit conflicting roles in the development, invasion, and metastasis of thyroid cancer (TC). Moreover, TAMs play a crucial role to the behavior of TC due to their high degree of infiltration and prognostic relevance. Generally, TAMs can be divided into two subgroups; M1-like TAMs are capable of directly kill tumor cells, and recruiting and activating other immune cells in the early stages of cancer. However, due to changes in the TME, M2-like TAMs gradually increase and promote tumor progression. This review aims to discuss the impact of TAMs on TC, including their role in tumor promotion, gene mutation, and other factors related to the polarization of TAMs. Finally, we will explore the M2-like TAM-centered therapeutic strategies, including chemotherapy, clinical trials, and combinatorial immunotherapy.
    Keywords:  Cancer metastasis; Immunotherapy; Thyroid cancer; Tumor microenvironment; Tumor-associated macrophages
  5. Biomed Pharmacother. 2023 Sep 30. pii: S0753-3322(23)01408-7. [Epub ahead of print]167 115610
      Esophageal squamous carcinoma (ESCC) is a prevalent and highly lethal malignant tumor, with a five-year survival rate of approximately 20 %. Tumor-associated macrophages (TAMs) are the most prominent immune cells in the tumor microenvironment (TME), comprising over 50 % of the tumor volume. TAMs can be polarized into two distinct phenotypes, M1-type and M2-type, through interactions with cancer cells. M2-type TAMs are more abundant than M1-type TAMs in the TME, contributing to tumor progression, such as tumor cell survival and the construction of an immunosuppressive environment. This review focuses on the role of TAMs in ESCC, including their polarization, impact on tumor proliferation, angiogenesis, invasion, migration, therapy resistance, and immunosuppression. In addition, we discuss the potential of targeting TAMs for clinical therapy in ESCC. A thorough comprehension of the molecular biology about TAMs is essential for the development of innovative therapeutic strategies to treat ESCC.
    Keywords:  Esophageal squamous carcinoma; Immune escape; Therapy resistance; Tumor-associated macrophage
  6. Curr Opin Biotechnol. 2023 Sep 30. pii: S0958-1669(23)00105-2. [Epub ahead of print]84 102995
      Despite the higher incidence of cancer with increasing age, few preclinical or clinical studies incorporate age. This, coupled with an aging world population, requires that we improve our understanding of how aging affects cancer development, progression, and treatment. One key area will be how the tumor microenvironment (TME) changes with age. Metabolite levels are an essential component of the TME, and they are affected by the metabolic requirements of the cells present and systemic metabolite availability. These factors are affected by aging, causing different TME metabolic states between young and older adults. In this review, we will summarize what is known about how aging impacts the TME metabolic state, and suggest how we can improve our understanding of it.
  7. Gan To Kagaku Ryoho. 2023 Sep;50(9): 958-959
      Cancer-associated fibroblasts(CAFs)remodel the extracellular matrix(ECM)and shape the tumor microenvironment (TME), resulting in immune escape and the promotion of tumor metastasis. Using an orthotopic tumor model of colorectal cancers(CRCs)in mice, we demonstrated that the single-cell RNA sequencing of orthotopic rectal tumors identified a subpopulation of CAFs that modulate the immune response. In this review, we report that understanding the role of CAFs in the TME concerning tumor immunity may lead to future avenues for CAF-targeted therapy.
  8. Clin Cancer Res. 2023 Oct 05.
      Cells in the tumor tumor microenvironment, including cancer-associated fibroblasts (CAFs), contribute to tumor growth and immune evasion. A recent study of Ewing sarcoma identified "CAF-like" tumor cells that mimic the pro-tumorigenic features of CAFs. These findings highlight the role of cell plasticity in tumor growth.
  9. Biomed Pharmacother. 2023 Sep 30. pii: S0753-3322(23)01420-8. [Epub ahead of print]167 115622
      The tumor microenvironment (TME), the "soil" on which tumor cells grow, has an important role in regulating the proliferation and metastasis of tumor cells as well as their response to treatment. Cancer-associated fibroblasts (CAFs), as the most abundant stromal cells of the TME, can not only directly alter the immunosuppressive effect of the TME through their own metabolism, but also influence the aggregation and function of immune cells by secreting a large number of cytokines and chemokines, reducing the body's immune surveillance of tumor cells and making them more prone to immune escape. Our study provides a comprehensive review of fibroblast chemotaxis, malignant transformation, metabolic characteristics, and interactions with immune cells. In addition, the current small molecule drugs targeting CAFs have been summarized, including both natural small molecules and targeted drugs for current clinical therapeutic applications. A complete review of the role of fibroblasts in TME from an immune perspective is presented, which has important implications in improving the efficiency of immunotherapy by targeting fibroblasts.
    Keywords:  Cancer-associated fibroblasts; Immune cells; Treatment; Tumor microenvironment
  10. J Transl Med. 2023 10 02. 21(1): 686
      Cancer stem cells (CSCs) have emerged as key contributors to tumor initiation, growth, and metastasis. In addition, CSCs play a significant role in inducing immune evasion, thereby compromising the effectiveness of cancer treatments. The reciprocal communication between CSCs and the tumor microenvironment (TME) is observed, with the TME providing a supportive niche for CSC survival and self-renewal, while CSCs, in turn, influence the polarization and persistence of the TME, promoting an immunosuppressive state. Consequently, these interactions hinder the efficacy of current cancer therapies, necessitating the exploration of novel therapeutic approaches to modulate the TME and target CSCs. In this review, we highlight the intricate strategies employed by CSCs to evade immune surveillance and develop resistance to therapies. Furthermore, we examine the dynamic interplay between CSCs and the TME, shedding light on how this interaction impacts cancer progression. Moreover, we provide an overview of advanced therapeutic strategies that specifically target CSCs and the TME, which hold promise for future clinical and translational studies in cancer treatment.
    Keywords:  Cancer immunotherapy; Cancer stem cell (CSC); Immune evasion; Myeloid-derived suppressor cells (MDSC); Therapy resistance; Tumor microenvironment (TME); Tumor-associated macrophage (TAM)
  11. Cancer Discov. 2023 Oct 06. OF1
      Brain tumor-associated neutrophils (TAN) exhibit unique myeloid cell-induced protumor phenotypes.
  12. Front Oncol. 2023 ;13 1289397
    Keywords:  bioenergetics; cancer; cancer/immune metabolism; metabolic disorder and cancer; metabolic imaging; metabolomics; tumor microenvironment
  13. Cell Oncol (Dordr). 2023 Sep 30.
      BACKGROUND: Tumor-associated macrophages, as the major immunocytes in solid tumors, show divided loyalty and remarkable plasticity in tumorigenesis. Once the M2-to-M1 repolarization is achieved, they could be switched from the supporters for tumor development into the guardians for host immunity. Meanwhile, Lipid metabolic reprogramming is demonstrated to be one of the most important hallmarks of tumor-associated macrophages, which plays a decisive role in regulating their phenotypes and functions to promote tumorigenesis and immunotherapy resistance. Therefore, targeting the lipid metabolism of TAMs may provide a new direction for anti-tumor strategies.CONCLUSION: In this review, we first summarized the origins, classifications and general lipid metabolic process of TAMs. Then we discussed the currently available drugs and interventions that target lipid metabolic disorders of TAMs, including those targeting lipid uptake, efflux, lipolysis, FAO and lipid peroxidation. Besides, based on the recent research status, we summarized the present challenges for this cancer immunotherapy, including the precise drug delivery system, the lipid metabolic heterogeneity, and the intricate lipid metabolic interactions in the TME, and we also proposed corresponding possible solutions. Collectively, we hope this review will give researchers a better understanding of the lipid metabolism of TAMs and lead to the development of corresponding anti-tumor therapies in the future.
    Keywords:  Cancer immunotherapy; Immunometabolism; Lipid metabolism; Tumor microenvironment; Tumor-associated macrophages
  14. Front Immunol. 2023 ;14 1283186
    Keywords:  biomarkers; cancer; checkpoint blockade; fibroblasts; imaging; immune oncology; immunotherapy; tumor microenvironment
  15. Environ Toxicol. 2023 Oct 04.
      The tumor microenvironment (TME) plays a critical role in tumor progression, with macrophages and tumor cells interacting within the TME, influencing cancer development. Despite the known anticancer properties of calcitriol, its role in the TME remains uncertain. This study aimed to explore the effects of calcitriol on macrophages and cancer cells in the TME and its impact on gastric cancer cell proliferation and cisplatin resistance. In vitro TME models were established using conditioned medium from gastric cancer cells (CCM) and macrophages (MCM) treated with or without calcitriol. The results revealed that calcitriol treatment suppressed the expression of glycolysis-related genes and proteins (GLUT1, HKII, LDHA) in MCM-induced gastric cancer cells, leading to increased cancer cell apoptosis and reduced viability, along with decreased Cyclin D1 gene expression. Moreover, calcitriol treatment inhibited mTOR activation in MCM-induced gastric cancer cells. Additionally, calcitriol hindered CCM-induced M2 macrophage polarization by reducing CD206 expression and increasing TNFα gene expression in THP1-derived macrophages, attenuating cisplatin resistance. These findings suggest that calcitriol may impede gastric cancer progression by targeting glycolysis and M2 macrophage polarization through the regulation of mTOR activation in the TME.
    Keywords:  M2 macrophage; calcitriol; gastric cancer; glycolysis; mTOR
  16. Breast Cancer. 2023 Oct 04.
      BACKGROUND: Programmed death-ligand 1 (PD-L1) plays important roles in the evasion of antitumor immunity. Because we observed the localization of PD-L1-positive (PD-L1+) cells in the marginal region of triple-negative breast cancer (TNBC) specimens, we hypothesized that the marginal microenvironment of TNBC would involve the induction of PD-L1+ cells.METHODS: One hundred and one TNBC surgical specimens were examined. We performed immunohistochemical (IHC) studies of PD-L1, CD68, CD8, and pan-cytokeratin in these specimens. We analyzed the localization of IHC-positive cells and the distance between these cells by histological spatial analysis.
    RESULTS: In 30.7% of TNBC specimens, PD-L1+ cells were located in the marginal region. Approximately three PD-L1+ cells accumulated around a single TNBC cell. Most PD-L1+ cells were located within 50 μm of TNBC cells. PD-L1+ cells were indicated to interact with TNBC cells in the marginal region. PD-L1+CD68+ cells were located in the marginal region, while CD68+ macrophages (MΦs) were observed either in the marginal region or the core region. PD-L1 expression in MΦs was induced in the marginal region. The colocalization of CD8+ T cells in the marginal region indicates that PD-L1 expression in MΦs would be induced by interaction with CD8+ T cells. Because CD8+ T cells are positive for CCL2, CCL2 may induce PD-L1 expression in MΦs.
    CONCLUSION: At the marginal microenvironment of TNBC, PD-L1 expression would be induced in MΦs by interaction with CD8+ T cells through CCL2. The interaction between PD-L1+ MΦs and TNBC cells would facilitate the growth of TNBC under antitumor immunity. These interactions would be potential targets for restoring antitumor immunity and suppressing TNBC progression.
    Keywords:  CD8+ T cell; Macrophage; Programmed death-ligand 1 (PD-L1); Triple-negative breast cancer (TNBC); Tumor microenvironment
  17. Mol Cancer. 2023 10 02. 22(1): 159
      Despite centuries since the discovery and study of cancer, cancer is still a lethal and intractable health issue worldwide. Cancer-associated fibroblasts (CAFs) have gained much attention as a pivotal component of the tumor microenvironment. The versatility and sophisticated mechanisms of CAFs in facilitating cancer progression have been elucidated extensively, including promoting cancer angiogenesis and metastasis, inducing drug resistance, reshaping the extracellular matrix, and developing an immunosuppressive microenvironment. Owing to their robust tumor-promoting function, CAFs are considered a promising target for oncotherapy. However, CAFs are a highly heterogeneous group of cells. Some subpopulations exert an inhibitory role in tumor growth, which implies that CAF-targeting approaches must be more precise and individualized. This review comprehensively summarize the origin, phenotypical, and functional heterogeneity of CAFs. More importantly, we underscore advances in strategies and clinical trials to target CAF in various cancers, and we also summarize progressions of CAF in cancer immunotherapy.
    Keywords:  CAF; Clinical trial; Immunotherapy; Microenvironment; Target
  18. Int J Radiat Oncol Biol Phys. 2023 Oct 01. pii: S0360-3016(23)04813-7. [Epub ahead of print]117(2S): S71
      PURPOSE/OBJECTIVE(S): Despite evidence of preclinical synergy between radiotherapy (RT) and immune checkpoint blockade (ICB), randomized trials of RT/ICB have demonstrated limited benefit in solid tumors. We performed single-cell RNA sequencing (scRNA-seq) and CITE-seq (cellular indexing of transcriptomes and epitopes) to address the discordance between preclinical and clinical data. We hypothesized that multiple orthogonal inhibitory immune pathways restrain the local and systemic efficacy of RT beyond T-cell oriented immune checkpoints.MATERIALS/METHODS: We used the EO771 syngeneic murine model of breast cancer to characterize the immune tumor microenvironment following RT with or without ICB. RT (16 Gy x 1) was delivered using the X-RAD SmART platform with CT image guidance. Neutralizing antibodies (anti-PD-1/Ly6G/Gr-1/CD47) were delivered by intraperitoneal injections. scRNA-seq analysis were performed by Seurat and BBrowser (BioTuring).
    RESULTS: We found that adaptive ICB (anti-PD-1) reprogrammed the immune response to RT by promoting an M1-like interferon-primed state (ISG15, CXCL10) in tumor associated macrophages (TAMs) and by increasing the late recruitment of intratumoral neutrophils. Given that neutrophils may drive resistance to RT in other models, we evaluated the effect of intratumoral neutrophil depletion using anti-Ly6G or anti-Gr-1 on the antitumor efficacy of RT/ICB. Both neutrophil depletion strategies led to enhanced tumor control and improved survival in advanced EO771 tumors compared to RT/ICB alone (P<0.001). In parallel to this approach, we found that TAMs upregulated several innate immune checkpoints including SIRPα in response to RT. Disruption of the SIRPα-CD47 interaction by anti-CD47 antibodies similarly enhanced the antitumor efficacy of RT/ICB by improving tumor control and survival (P<0.001). Using scRNA-seq and unbiased clustering, we found that anti-CD47 eliminated an entire cluster of chronically inflamed TAMs, characterized by pro-inflammatory markers (IL1A, NOS2) and chemokines (CCL3, CXCL1/2/3). Anti-CD47 also reduced intratumoral neutrophils by eliminating a cluster of pathologically activated neutrophils, termed myeloid-derived suppressor cells (PMN-MDSCs) that expressed several markers of ferroptosis (TFRC, PTGS2, SLC3A2). Consistent with the potent immunosuppressive capacity of PMN-MDSCs, we found that anti-CD47 increased tumor-infiltrating lymphocytes including central memory TCF7+ T cells and CD19+ B cells. Lastly, by inference and analysis of cell-cell communication (CellChat), we found that anti-CD47 strengthened the interactions between TAMs and CD8+ T cells compared to RT/ICB alone.
    CONCLUSION: Our data collectively indicate that resistance to RT/ICB in the EO771 model Is driven by innate immune cells including neutrophils and chronically inflamed TAMs. Targeted disruption of the CD47-SIRPα axis is a promising approach to overcoming immune resistance by reprogramming TAMs and eliminating PMN-MDSCs.
  19. Front Biosci (Landmark Ed). 2023 Sep 15. 28(9): 206
      Adoptive chimeric antigen receptor (CAR) T cells designed to recognize specific tumor antigens have shown promising results in cancer therapy. While CAR T cell therapy has demonstrated notable clinical effectiveness for hematologic disease, efforts to develop therapies for solid tumors, including glioblastoma (GBM), have been hampered by heterogeneity, an immunosuppressive tumor microenvironment, and difficulty in trafficking. Several specific tumor antigens, such as IL13Rα2, EGFRvIII, and HER2, have been attempted in clinical trials; however, limited efficacy has been observed. In this review, we discuss the current status of CAR T therapy for GBM in clinical trials and highlight the potential target antigens for CAR T cells. Additionally, we summarize the mechanisms used to enhance their efficacy and explore the challenges and future prospects of CAR T cell therapy for GBM.
    Keywords:  CAR T; cancer therapy; cell therapy; glioblastoma; immunotherapy
  20. Med Oncol. 2023 Oct 01. 40(11): 313
      Treatment with chimeric antigen receptor (CAR) T cells indicated remarkable clinical responses with liquid cancers such as hematological malignancies; however, their therapeutic efficacy faced with many challenges in solid tumors due to severe toxicities, antigen evasion, restricted and limited tumor tissue trafficking and infiltration, and, more importantly, immunosuppressive tumor microenvironment (TME) factors that impair the CAR T-cell function adds support survival of cancer stem cells (CSCs), responsible for tumor recurrence and resistance to current cancer therapies. Therefore, in-depth identification of TME and development of more potent CAR platform targeting CSCs may overcome the raised challenges, as presented in this review. We also discuss recent stemness-based innovations in CAR T-cell production and engineering to improve their efficacy in vivo, and finally, we propose solutions and strategies such as oncolytic virus-based therapy and combination therapy to revive the function of CAR T-cell therapy, especially in TME of solid tumors in future.
    Keywords:  Adoptive cell therapy; Cancer stem cell; Oncolytic virus; Stemness; Tumor microenvironment; iPSC
  21. Front Endocrinol (Lausanne). 2023 ;14 1217875
      Obesity and type 2 diabetes are chronic metabolic diseases that impact tens to hundreds of millions of adults, especially in developed countries. Each condition is associated with an elevated risk of breast cancer and with a poor prognosis after treatment. The mechanisms connecting poor metabolic health to breast cancer are numerous and include hyperinsulinemia, inflammation, excess nutrient availability, and adipose tissue dysfunction. Here, we focus on adipose tissue, highlighting important roles for both adipocytes and fibroblasts in breast cancer progression. One potentially important mediator of adipose tissue effects on breast cancer is the fibroblast growth factor receptor (FGFR) signaling network. Among the many roles of FGFR signaling, we postulate that key mechanisms driving aggressive breast cancer include epithelial-to-mesenchymal transition and cellular metabolic reprogramming. We also pose existing questions that may help better understand breast cancer biology in people with obesity, type 2 diabetes, and poor metabolic health.
    Keywords:  adipose; breast cancer; diabetes; fibroblast growth factor; obesity