Immune Cell Metabolism in Tumor Microenvironment

AbstractAltered energy metabolism of cancer cells shapes the immune cell response in the tumor microenvironment that facilitates tumor progression. Herein, we reported the novel of tumor cell-expressed Piwi Like RNA-Mediated Gene Silencing 1 (PIWIL1) in mediating the crosstalk of fatty acid metabolism and immune response of human hepatocellular carcinoma (HCC). PIWIL1 expression in HCC was increased compared to normal hepatic tissues and was positively correlated with the proliferation rate of HCC cell lines. PIWIL1 overexpression accelerated in vitro proliferation and in vivo growth of HCC tumors, while PIWIL1 knockdown showed opposite effects. PIWIL1 increased oxygen consumption and energy production via fatty acid metabolism without altering aerobic glycolysis. Inhibition of fatty acid metabolism abolished PIWIL1-induced HCC proliferation and growth. RNA-seq analysis revealed that immune system regulation might be involved, which was echoed by the experimental observation that PIWIL1-overexpressing HCC cells attracted myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. MDSCs depletion reduced the proliferation and growth of PIWIL1-overexpressing HCC tumors. Complement C3, whose secretion was induced by PIWIL1 in HCC cells, mediates the interaction of HCC cells with MDSCs by activated p38 MAPK signaling in MDSCs, which in turn initiated expression of immunosuppressive cytokine IL10. Neutralizing IL10 secretion reduced the immunosuppressive activity of MDSCs in the microenvironment of PIWIL1-overexpressing HCC. Taken together, our study unraveled the critical role of PIWIL1 in initiating the interaction of cancer cell metabolism and immune cell response in HCC. Tumor cells-expressed PIWIL1 may be a potential target for the development of novel HCC treatment.

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Recent Advancements on Immunomodulatory Mechanisms of Resveratrol in Tumor Microenvironment

Molecules ◽

10.3390/molecules26051343 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1343

Author(s):

Gagan Chhabra ◽

Chandra K. Singh ◽

Deeba Amiri ◽

Neha Akula ◽

Nihal Ahmad

Keyword(s):

Tumor Microenvironment ◽

Immune Cell ◽

Cancer Therapies ◽

Regulatory Cells ◽

Immunomodulatory Effects ◽

Cancer Management ◽

Natural Agents ◽

Anticancer Effects ◽

Cancer Types ◽

Immune Related Genes

Immunomodulation of the tumor microenvironment is emerging as an important area of research for the treatment of cancer patients. Several synthetic and natural agents are being investigated for their ability to enhance the immunogenic responses of immune cells present in the tumor microenvironment to impede tumor cell growth and dissemination. Among them, resveratrol, a stilbenoid found in red grapes and many other natural sources, has been studied extensively. Importantly, resveratrol has been shown to possess activity against various human diseases, including cancer. Mechanistically, resveratrol has been shown to regulate an array of signaling pathways and processes involving oxidative stress, inflammation, apoptosis, and several anticancer effects. Furthermore, recent research suggests that resveratrol can regulate various cellular signaling events including immune cell regulation, cytokines/chemokines secretion, and the expression of several other immune-related genes. In this review, we have summarized recent findings on resveratrol’s effects on immune regulatory cells and associated signaling in various cancer types. Numerous immunomodulatory effects of resveratrol suggest it may be useful in combination with other cancer therapies including immunotherapy for effective cancer management.

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ADAMTS12 acts as a tumor microenvironment related cancer promoter in gastric cancer

Scientific Reports ◽

10.1038/s41598-021-90330-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yangming Hou ◽

Yingjuan Xu ◽

Dequan Wu

Keyword(s):

Gastric Cancer ◽

Tumor Microenvironment ◽

Immune Cell ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Tumor Promoter ◽

Protein Protein Interaction ◽

Oxidative Phosphorylation Pathway ◽

Cox Proportional Hazard Regression

AbstractThe infiltration degree of immune and stromal cells has been shown clinically significant in tumor microenvironment (TME). However, the utility of stromal and immune components in Gastric cancer (GC) has not been investigated in detail. In the present study, ESTIMATE and CIBERSORT algorithms were applied to calculate the immune/stromal scores and the proportion of tumor-infiltrating immune cell (TIC) in GC cohort, including 415 cases from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) were screened by Cox proportional hazard regression analysis and protein–protein interaction (PPI) network construction. Then ADAMTS12 was regarded as one of the most predictive factors. Further analysis showed that ADAMTS12 expression was significantly higher in tumor samples and correlated with poor prognosis. Gene Set Enrichment Analysis (GSEA) indicated that in high ADAMTS12 expression group gene sets were mainly enriched in cancer and immune-related activities. In the low ADAMTS12 expression group, the genes were enriched in the oxidative phosphorylation pathway. CIBERSORT analysis for the proportion of TICs revealed that ADAMTS12 expression was positively correlated with Macrophages M0/M1/M2 and negatively correlated with T cells follicular helper. Therefore, ADAMTS12 might be a tumor promoter and responsible for TME status and tumor energy metabolic conversion.

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492 Integration of high dimensional datasets in an immunocompetent mammary mouse model reveals pathways of tolerance and resistance to immune checkpoint blockade

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0492 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A528-A528

Author(s):

Lin Ma ◽

Jian-Hua Mao ◽

Mary Helen Barcellos-Hoff ◽

Jade Moore

Keyword(s):

Tumor Microenvironment ◽

Immune Cells ◽

Transforming Growth Factor ◽

Immune Cell ◽

Systemic Disease ◽

Ct Imaging ◽

High Dimensional ◽

Cytokine Signaling ◽

Immune Infiltrate ◽

Pet Ct

BackgroundCheckpoint inhibitors can induce robust and durable responses in a subset of patients. Extending this benefit to more patients could be facilitated by better understanding of how interacts with immune cells with the tumor microenvironment, which is a critical barrier to control both local and systemic disease. The composition and pattern of the immune infiltrate associates with the likelihood of response to immunotherapy. Inflamed tumors that exhibit a brisk immune cell infiltrate are responsive, while those in which immune cells are completely or partially excluded are not. Transforming growth factor β (TGFβ) is immunosuppressive and associated with the immune excluded phenotype.MethodsUsing an immune competent mammary tumor derived transplant (mTDT) model recently developed in our lab, exhibits inflamed, excluded or deserts immune infiltrate phenotypes based on localization of CD8 lymphocytes. Using whole transcriptome deep sequencing, cytof, and PET-CT imaging, we evaluated the tumor, microenvironment, and immune pathway activation among immune infiltrate phenotypes.ResultsThree distinct inflamed tumors phenotypes were identified: ‘classically’ inflamed characterized by pathway evidence of increased CD8+ T cells and decreased PD-L1 expression, inflamed tumors with pathways indicative of neovascularization and STAT3 signaling and reduced T cell mobilization, and an inflamed tumor with increased immunosuppressive myeloid phenotypes. Excluded tumors were characterized by TGFβ gene expression and pro-inflammatory cytokine signaling (e.g. TNFα, IL1β), associated with decreased leukocytes homing and increased immune cell death of cells. We visualized and quantified TGFβ activity using PET-CT imaging of 89Zr-fresolimumab, a TGFβ neutralizing antibody. TGFβ activity was significantly increased in excluded tumors compared to inflamed or desert tumors, which was supported by quantitative pathology (Perkin Elmer) of its canonical signaling target, phosphorylated SMAD2 (pSMAD2). pSMAD2 was positively correlated with PD-L1 expression in the stroma of excluded tumors. In contrast, in inflamed tumors, TGFβ activity positively correlated with increased F4/80 positive macrophages and negatively correlated with expression of PD-L1. CyTOF analysis of tumor and spleen immune phenotypes revealed increased trafficking of myeloid cells in mice bearing inflamed tumors compared to excluded and deserts.ConclusionsThe immunocompetent mTDT provides a model that bridges the gap between the immune landscape and tumor microenvironment. Integration of these high-dimensional data with further studies of response to immunotherapies will help to identify tumor features that favor response to treatment or the means to convert those that are unresponsive.

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Tumor morphology and location associate with immune cell composition in pleomorphic sarcoma

Cancer Immunology Immunotherapy ◽

10.1007/s00262-021-02935-2 ◽

2021 ◽

Author(s):

Rosanna L. Wustrack ◽

Evans Shao ◽

Joey Sheridan ◽

Melissa Zimel ◽

Soo-Jin Cho ◽

...

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

Cd8 T Cells ◽

Tumor Size ◽

Immune Cell ◽

Human Cancer ◽

Soft Tissue Sarcomas ◽

Inverse Correlation ◽

Anatomical Location ◽

Pleomorphic Sarcoma

Abstract Background Soft-tissue sarcomas (STS) are a rare group of mesenchymal malignancies that account for approximately 1% of adult human cancer. Undifferentiated pleomorphic sarcoma (UPS) is one of the most common subtypes of adult STS. Clinical stratification of UPS patients has not evolved for decades and continues to rely on tumor-centric metrics including tumor size and depth. Our understanding of how the tumor microenvironment correlates to these clinicopathologic parameters remains limited. Methods Here, we performed single-cell flow cytometric immune-based profiling of 15 freshly resected UPS tumors and integrated this analysis with clinical, histopathologic, and outcomes data using both a prospective and retrospective cohort of UPS patients. Results We uncovered a correlation between physiologic and anatomic properties of UPS tumors and the composition of immune cells in the tumor microenvironment. Specifically, we identified an inverse correlation between tumor-infiltrating CD8 + T cells and UPS tumor size; and a positive correlation between tumor-infiltrating CD8 + T cells and overall survival. Moreover, we demonstrate an association between anatomical location (deep or superficial) and frequency of CD4 + PD1hi infiltrating T cells in UPS tumors. Conclusions Our study provides an immune-based analysis of the tumor microenvironment in UPS patients and describes the different composition of tumor infiltrating lymphocytes based on size and tumor depth.

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705 Anti-tumor activity of CB-668, a potent, selective and orally bioavailable small-molecule inhibitor of the immuno-suppressive enzyme Interleukin 4 (IL-4)-Induced Gene 1 (IL4I1)

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0705 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A747-A747

Author(s):

Andrew MacKinnon ◽

Deepthi Bhupathi ◽

Jason Chen ◽

Tony Huang ◽

Weiqun Li ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Tumor Microenvironment ◽

Immune Cell ◽

Interleukin 4 ◽

Mouse Tumor ◽

Syngeneic Mouse ◽

Molecule Inhibitor ◽

Anti Tumor Activity ◽

Mouse Tumor Models

BackgroundTumors evade destruction by the immune system through multiple mechanisms including altering metabolism in the tumor microenvironment. Metabolic control of immune responses occurs through depletion of essential nutrients or accumulation of toxic metabolites that impair immune cell function and promote tumor growth. The secreted enzyme interleukin 4 (IL-4)-induced gene 1 (IL4I1) is an L-phenylalanine oxidase that catabolizes phenylalanine and produces phenyl-pyruvate and hydrogen peroxide. IL4I1 regulates several aspects of adaptive immunity in mice, including inhibition of cytotoxic T cells through its production of hydrogen peroxide (reviewed in1). In human tumors, IL4I1 expression is significantly elevated relative to normal tissues and is notably high in ovarian tumors and B cell lymphomas. Motivated by the hypothesis that IL4I1 is an immuno-metabolic enzyme that suppresses anti-tumor immunity, we discovered CB-668, the first known small-molecule inhibitor of IL4I1.MethodsIL4I1 enzymatic activity was measured using an HRP-coupled enzyme assay. RNA in-situ hybridization was carried out on the RNAScope platform. Syngeneic mouse tumor models were used to evaluate the anti-tumor activity of CB-668. The level of phenyl-pyruvate in tumor homogenates was measured by LC/MS.ResultsOur clinical candidate, CB-668 is a potent and selective non-competitive inhibitor of IL4I1 (IC50 = 15 nM). CB-668 has favorable in vitro ADME properties and showed low clearance and high oral bioavailability in rodents. Twice-daily oral administration of CB-668 was well-tolerated in mice and resulted in single-agent anti-tumor activity in the syngeneic mouse tumor models B16-F10, A20, and EG7. Oral CB-668 administration reduced the levels of phenyl-pyruvate in the tumor, consistent with inhibition of IL4I1 enzymatic activity. Anti-tumor activity of CB-668 was immune cell-mediated since efficacy was abrogated in CD8-depleted mice, and CB-668 treatment caused increased expression of pro-inflammatory immune genes in the tumor. Moreover, CB-668 had no direct anti-proliferative activity on tumor cells grown in vitro (IC50 > 50 µM). CB-668 also favorably combined with anti-PD-L1 therapy to reduce tumor growth in the B16-F10 tumor model.ConclusionsThese data support an immune-mediated anti-tumor effect of IL4I1 inhibition by CB-668, and suggest inhibition of IL4I1 represents a novel strategy for cancer immuno-therapy.ReferencesMolinier-Frenkel V, Prévost-Blondel A, and Castellano F. The IL4I1 Enzyme: A New Player in the Immunosuppressive Tumor Microenvironment. Cells 2019;8:1–9.

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Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy

Oncogene ◽

10.1038/s41388-021-01846-x ◽

2021 ◽

Author(s):

Audrey Lequeux ◽

Muhammad Zaeem Noman ◽

Malina Xiao ◽

Kris Van Moer ◽

Meriem Hasmim ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cancer Immunotherapy ◽

Transcriptional Activity ◽

Immune Cell ◽

Tumor Resistance ◽

Combination Strategy ◽

Immune Effector ◽

Effector Cells ◽

Melanoma Patients ◽

The Impact

AbstractHypoxia is a key factor responsible for the failure of therapeutic response in most solid tumors and promotes the acquisition of tumor resistance to various antitumor immune effectors. Reshaping the hypoxic immune suppressive tumor microenvironment to improve cancer immunotherapy is still a relevant challenge. We investigated the impact of inhibiting HIF-1α transcriptional activity on cytotoxic immune cell infiltration into B16-F10 melanoma. We showed that tumors expressing a deleted form of HIF-1α displayed increased levels of NK and CD8+ effector T cells in the tumor microenvironment, which was associated with high levels of CCL2 and CCL5 chemokines. We showed that combining acriflavine, reported as a pharmacological agent preventing HIF-1α/HIF-1β dimerization, dramatically improved the benefit of cancer immunotherapy based on TRP-2 peptide vaccination and anti-PD-1 blocking antibody. In melanoma patients, we revealed that tumors exhibiting high CCL5 are less hypoxic, and displayed high NK, CD3+, CD4+ and CD8+ T cell markers than those having low CCL5. In addition, melanoma patients with high CCL5 in their tumors survive better than those having low CCL5. This study provides the pre-clinical proof of concept for a novel triple combination strategy including blocking HIF-1α transcription activity along vaccination and PD-1 blocking immunotherapy.

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Impact of obesity and SARS-CoV-2 infection: implications for host defence - a living review

Oxford Open Immunology ◽

10.1093/oxfimm/iqab001 ◽

2021 ◽

Vol 2 (1) ◽

Author(s):

Felix Clemens Richter ◽

Aljawharah Alrubayyi ◽

Alicia Teijeira Crespo ◽

Sarah Hulin-Curtis ◽

Keyword(s):

Lipid Metabolism ◽

Influenza A ◽

Immune Cell ◽

Cell Metabolism ◽

Low Grade ◽

Obese Patients ◽

Healthy Weight ◽

Virus Infections ◽

Immune Alterations ◽

And Function

Abstract The role of obesity in the pathophysiology of respiratory virus infections has become particularly apparent during the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, where obese patients are twice as likely to suffer from severe coronavirus disease 2019 (COVID-19) than healthy weight individuals. Obesity results in disruption of systemic lipid metabolism promoting a state of chronic low-grade inflammation. However, it remains unclear how these underlying metabolic and cellular processes promote severe SARS-CoV-2 infection. Emerging data in SARS-CoV-2 and Influenza A virus (IAV) infections show that viruses can further subvert the host’s altered lipid metabolism and exploit obesity-induced alterations in immune cell metabolism and function to promote chronic inflammation and viral propagation. In this review, we outline the systemic metabolic and immune alterations underlying obesity and discuss how these baseline alterations impact the immune response and disease pathophysiology. A better understanding of the immunometabolic landscape of obese patients may aid better therapies and future vaccine design.

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When Cells Suffocate: Autophagy in Cancer and Immune Cells under Low Oxygen

International Journal of Cell Biology ◽

10.1155/2011/470597 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 16

Author(s):

Katrin Schlie ◽

Jaeline E. Spowart ◽

Luke R. K. Hughson ◽

Katelin N. Townsend ◽

Julian J. Lum

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Immune Cells ◽

Immune Cell ◽

Treatment Strategies ◽

Patient Treatment ◽

Low Oxygen ◽

Tumor Environment ◽

And Function ◽

The Impact

Hypoxia is a signature feature of growing tumors. This cellular state creates an inhospitable condition that impedes the growth and function of all cells within the immediate and surrounding tumor microenvironment. To adapt to hypoxia, cells activate autophagy and undergo a metabolic shift increasing the cellular dependency on anaerobic metabolism. Autophagy upregulation in cancer cells liberates nutrients, decreases the buildup of reactive oxygen species, and aids in the clearance of misfolded proteins. Together, these features impart a survival advantage for cancer cells in the tumor microenvironment. This observation has led to intense research efforts focused on developing autophagy-modulating drugs for cancer patient treatment. However, other cells that infiltrate the tumor environment such as immune cells also encounter hypoxia likely resulting in hypoxia-induced autophagy. In light of the fact that autophagy is crucial for immune cell proliferation as well as their effector functions such as antigen presentation and T cell-mediated killing of tumor cells, anticancer treatment strategies based on autophagy modulation will need to consider the impact of autophagy on the immune system.

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