Tumor Microenvironment: A Metabolic Player that Shapes the Immune Response

Immune cells survey and patrol throughout the body and sometimes take residence in niche environments with distinct cellular subtypes and nutrients that may fluctuate from those in which they matured. Rooted in immune cell physiology are metabolic pathways and metabolites that not only deliver substrates and energy for growth and survival, but also instruct effector functions and cell differentiation. Unlike cancer cells, immune cells are not subject to a “Darwinian evolutionary pressure” that would allow them to adapt to developing tumors but are often irrevocably affected to local nutrient deprivation. Thus, immune cells must metabolically adapt to these changing conditions in order to perform their necessary functions. On the other hand, there is now a growing appreciation that metabolic changes occurring in cancer cells can impact on immune cell functionality and contribute to tumor immune evasion, and as such, there is a considerable and growing interest in developing techniques that target metabolism for immunotherapy. In this review, we discuss the metabolic plasticity displayed by innate and adaptive immune cells and highlight how tumor-derived lactate and tumor acidity restrict immunity. To our knowledge, this review outlines the most recent insights on how tumor microenvironment metabolically instructs immune responsiveness.

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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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Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion

Science ◽

10.1126/science.aav2588 ◽

2019 ◽

Vol 366 (6468) ◽

pp. 1013-1021 ◽

Cited By ~ 96

Author(s):

Robert D. Leone ◽

Liang Zhao ◽

Judson M. Englert ◽

Im-Meng Sun ◽

Min-Hee Oh ◽

...

Keyword(s):

T Cells ◽

Cancer Cells ◽

Cell Function ◽

Immune Cell ◽

Effector T Cells ◽

Tumor Immune Evasion ◽

Metabolic Characteristics ◽

Metabolic Plasticity ◽

Tumor Bearing ◽

Immunosuppressive Microenvironment

The metabolic characteristics of tumors present considerable hurdles to immune cell function and cancer immunotherapy. Using a glutamine antagonist, we metabolically dismantled the immunosuppressive microenvironment of tumors. We demonstrate that glutamine blockade in tumor-bearing mice suppresses oxidative and glycolytic metabolism of cancer cells, leading to decreased hypoxia, acidosis, and nutrient depletion. By contrast, effector T cells responded to glutamine antagonism by markedly up-regulating oxidative metabolism and adopting a long-lived, highly activated phenotype. These divergent changes in cellular metabolism and programming form the basis for potent antitumor responses. Glutamine antagonism therefore exposes a previously undefined difference in metabolic plasticity between cancer cells and effector T cells that can be exploited as a “metabolic checkpoint” for tumor immunotherapy.

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Metabolites in the Tumor Microenvironment Reprogram Functions of Immune Effector Cells Through Epigenetic Modifications

Frontiers in Immunology ◽

10.3389/fimmu.2021.641883 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yijia Li ◽

Yangzhe Wu ◽

Yi Hu

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Immune Cells ◽

Expression Patterns ◽

Immune Effector ◽

Effector Cells ◽

Cell Functions ◽

Metabolic Plasticity ◽

Signal Transduction Networks ◽

Immune Effector Cells

Cellular metabolism of both cancer and immune cells in the acidic, hypoxic, and nutrient-depleted tumor microenvironment (TME) has attracted increasing attention in recent years. Accumulating evidence has shown that cancer cells in TME could outcompete immune cells for nutrients and at the same time, producing inhibitory products that suppress immune effector cell functions. Recent progress revealed that metabolites in the TME could dysregulate gene expression patterns in the differentiation, proliferation, and activation of immune effector cells by interfering with the epigenetic programs and signal transduction networks. Nevertheless, encouraging studies indicated that metabolic plasticity and heterogeneity between cancer and immune effector cells could provide us the opportunity to discover and target the metabolic vulnerabilities of cancer cells while potentiating the anti-tumor functions of immune effector cells. In this review, we will discuss the metabolic impacts on the immune effector cells in TME and explore the therapeutic opportunities for metabolically enhanced immunotherapy.

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Shaping Immune Responses in the Tumor Microenvironment of Ovarian Cancer

Frontiers in Immunology ◽

10.3389/fimmu.2021.692360 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xin Luo ◽

Jing Xu ◽

Jianhua Yu ◽

Ping Yi

Keyword(s):

Ovarian Cancer ◽

Tumor Microenvironment ◽

Immune Responses ◽

Cancer Cells ◽

Disease Progression ◽

Immune Cells ◽

Biomarker Discovery ◽

Immune Cell ◽

Ovarian Cancer Cells ◽

Cancer Tumor

Reciprocal signaling between immune cells and ovarian cancer cells in the tumor microenvironment can alter immune responses and regulate disease progression. These signaling events are regulated by multiple factors, including genetic and epigenetic alterations in both the ovarian cancer cells and immune cells, as well as cytokine pathways. Multiple immune cell types are recruited to the ovarian cancer tumor microenvironment, and new insights about the complexity of their interactions have emerged in recent years. The growing understanding of immune cell function in the ovarian cancer tumor microenvironment has important implications for biomarker discovery and therapeutic development. This review aims to describe the factors that shape the phenotypes of immune cells in the tumor microenvironment of ovarian cancer and how these changes impact disease progression and therapy.

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Cell Programmed Nutrient Partitioning in the Tumor Microenvironment

10.1101/2020.08.10.238428 ◽

2020 ◽

Author(s):

BI Reinfeld ◽

MZ Madden ◽

MM Wolf ◽

A Chytil ◽

JE Bader ◽

...

Keyword(s):

Tumor Microenvironment ◽

Glucose Uptake ◽

Cancer Cells ◽

Immune Cells ◽

Immune Cell ◽

Cell Types ◽

Specific Cell ◽

Mtorc1 Signaling ◽

Nutrient Partitioning ◽

Glutamine Uptake

The tumor microenvironment (TME) includes transformed cancer and infiltrating immune cells1,2. Cancer cells can consume large quantities of glucose through Warburg metabolism3,4 that can be visualized with positron emission tomography (PET). While infiltrating immune cells also rely on glucose, disruptions to metabolism can contribute to tumor immunological evasion5–9. How immune cell metabolism is programmed or restrained by competition with cancer cells for nutrients, remains uncertain. Here we used PET tracers to measure the accessibility of glucose and glutamine to cell subsets in the TME. Surprisingly, myeloid cells including macrophages were the greatest consumers of intra-tumoral glucose, followed by T cells and cancer cells. Cancer cells, in contrast, had the highest glutamine uptake. This distinct nutrient partitioning was programmed through selective mTORC1 signaling and glucose or glutamine-related gene expression. Inhibition of glutamine uptake enhanced glucose uptake across tumor resident cell types and shifted macrophage phenotype, demonstrating glucose is not limiting in the TME. Thus, cancer cells are not the only cells in tumors which exhibit high glucose uptake in vivo and instead preferentially utilize glutamine over other cell types. We observe that intrinsic cellular programs can play a major role in the use of some nutrients. Together, these data argue cell selective partitioning of glucose and glutamine can be exploited to develop therapies and imaging strategies to alter the metabolic programs of specific cell populations in the TME.

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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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Platelets, immune cells and the coagulation cascade; friend or foe of the circulating tumour cell?

Molecular Cancer ◽

10.1186/s12943-021-01347-1 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Mark P. Ward ◽

Laura E. Kane ◽

Lucy A. Norris ◽

Bashir M. Mohamed ◽

Tanya Kelly ◽

...

Keyword(s):

Cancer Cells ◽

Immune Cells ◽

Immune Cell ◽

Circulatory System ◽

Morphological Characteristics ◽

Metastatic Potential ◽

Coagulation Cascade ◽

Molecular Profile ◽

Great Promise ◽

Liquid Biopsies

AbstractCancer cells that transit from primary tumours into the circulatory system are known as circulating tumour cells (CTCs). These cancer cells have unique phenotypic and genotypic characteristics which allow them to survive within the circulation, subsequently extravasate and metastasise. CTCs have emerged as a useful diagnostic tool using “liquid biopsies” to report on the metastatic potential of cancers. However, CTCs by their nature interact with components of the blood circulatory system on a constant basis, influencing both their physical and morphological characteristics as well as metastatic capabilities. These properties and the associated molecular profile may provide critical diagnostic and prognostic capabilities in the clinic. Platelets interact with CTCs within minutes of their dissemination and are crucial in the formation of the initial metastatic niche. Platelets and coagulation proteins also alter the fate of a CTC by influencing EMT, promoting pro-survival signalling and aiding in evading immune cell destruction. CTCs have the capacity to directly hijack immune cells and utilise them to aid in CTC metastatic seeding processes. The disruption of CTC clusters may also offer a strategy for the treatment of advance staged cancers. Therapeutic disruption of these heterotypical interactions as well as direct CTC targeting hold great promise, especially with the advent of new immunotherapies and personalised medicines. Understanding the molecular role that platelets, immune cells and the coagulation cascade play in CTC biology will allow us to identify and characterise the most clinically relevant CTCs from patients. This will subsequently advance the clinical utility of CTCs in cancer diagnosis/prognosis.

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In Vitro Evaluation of CD276-CAR NK-92 Functionality, Migration and Invasion Potential in the Presence of Immune Inhibitory Factors of the Tumor Microenvironment

Cells ◽

10.3390/cells10051020 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1020

Author(s):

Stefan Grote ◽

Guillermo Ureña-Bailén ◽

Kenneth Chun-Ho Chan ◽

Caroline Baden ◽

Markus Mezger ◽

...

Keyword(s):

Tumor Microenvironment ◽

Solid Tumors ◽

Immune Cells ◽

Immune Cell ◽

Nk Cell ◽

Migration And Invasion ◽

Cellular Immunotherapy ◽

Knock Out ◽

Immunosuppressive Tumor Microenvironment

Background: Melanoma is the most lethal of all skin-related cancers with incidences continuously rising. Novel therapeutic approaches are urgently needed, especially for the treatment of metastasizing or therapy-resistant melanoma. CAR-modified immune cells have shown excellent results in treating hematological malignancies and might represent a new treatment strategy for refractory melanoma. However, solid tumors pose some obstacles for cellular immunotherapy, including the identification of tumor-specific target antigens, insufficient homing and infiltration of immune cells as well as immune cell dysfunction in the immunosuppressive tumor microenvironment (TME). Methods: In order to investigate whether CAR NK cell-based immunotherapy can overcome the obstacles posed by the TME in melanoma, we generated CAR NK-92 cells targeting CD276 (B7-H3) which is abundantly expressed in solid tumors, including melanoma, and tested their effectivity in vitro in the presence of low pH, hypoxia and other known factors of the TME influencing anti-tumor responses. Moreover, the CRISPR/Cas9-induced disruption of the inhibitory receptor NKG2A was assessed for its potential enhancement of NK-92-mediated anti-tumor activity. Results: CD276-CAR NK-92 cells induced specific cytolysis of melanoma cell lines while being able to overcome a variety of the immunosuppressive effects normally exerted by the TME. NKG2A knock-out did not further improve CAR NK-92 cell-mediated cytotoxicity. Conclusions: The strong cytotoxic effect of a CD276-specific CAR in combination with an “off-the-shelf” NK-92 cell line not being impaired by some of the most prominent negative factors of the TME make CD276-CAR NK-92 cells a promising cellular product for the treatment of melanoma and beyond.

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Tuning cancer fate: the unremitting role of host immunity

Open Biology ◽

10.1098/rsob.170006 ◽

2017 ◽

Vol 7 (4) ◽

pp. 170006 ◽

Cited By ~ 22

Author(s):

B. Calì ◽

B. Molon ◽

A. Viola

Keyword(s):

Immune Cells ◽

Immune Cell ◽

Tumour Progression ◽

Host Immunity ◽

Adaptive Immune ◽

Adaptive Immune Cells ◽

Immune Mediated ◽

Immune Cell Subsets ◽

Therapeutic Protocols

Host immunity plays a central and complex role in dictating tumour progression. Solid tumours are commonly infiltrated by a large number of immune cells that dynamically interact with the surrounding microenvironment. At first, innate and adaptive immune cells successfully cooperate to eradicate microcolonies of transformed cells. Concomitantly, surviving tumour clones start to proliferate and harness immune responses by specifically hijacking anti-tumour effector mechanisms and fostering the accumulation of immunosuppressive immune cell subsets at the tumour site. This pliable interplay between immune and malignant cells is a relentless process that has been concisely organized in three different phases: elimination, equilibrium and escape. In this review, we aim to depict the distinct immune cell subsets and immune-mediated responses characterizing the tumour landscape throughout the three interconnected phases. Importantly, the identification of key immune players and molecules involved in the dynamic crosstalk between tumour and immune system has been crucial for the introduction of reliable prognostic factors and effective therapeutic protocols against cancers.

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Semaphorin Signaling in Cancer-Associated Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms20020377 ◽

2019 ◽

Vol 20 (2) ◽

pp. 377 ◽

Cited By ~ 12

Author(s):

Giulia Franzolin ◽

Luca Tamagnone

Keyword(s):

Immune Response ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Disease Progression ◽

Tumor Cells ◽

Cross Talk ◽

Immune Cells ◽

Major Element ◽

Inflammatory Cells ◽

Anti Cancer

The inflammatory and immune response elicited by the growth of cancer cells is a major element conditioning the tumor microenvironment, impinging on disease progression and patients’ prognosis. Semaphorin receptors are widely expressed in inflammatory cells, and their ligands are provided by tumor cells, featuring an intense signaling cross-talk at local and systemic levels. Moreover, diverse semaphorins control both cells of the innate and the antigen-specific immunity. Notably, semaphorin signals acting as inhibitors of anti-cancer immune response are often dysregulated in human tumors, and may represent potential therapeutic targets. In this mini-review, we provide a survey of the best known semaphorin regulators of inflammatory and immune cells, and discuss their functional impact in the tumor microenvironment.

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