scholarly journals Metabolism of Immune Cells in the Tumor Microenvironment

2021 ◽  
pp. 173-185
Author(s):  
Jin G. Jung ◽  
Anne Le
Keyword(s):  
Extracellular Matrix ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Immune Cells ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Biology ◽  
Determinant Factor

AbstractThe tumor microenvironment (TME) is a complex biological structure surrounding tumor cells and includes blood vessels, immune cells, fibroblasts, adipocytes, and extracellular matrix (ECM) [1, 2]. These heterogeneous surrounding structures provide nutrients, metabolites, and signaling molecules to provide a cancer-friendly environment. The metabolic interplay between immune cells and cancer cells in the TME is a key feature not only for understanding tumor biology but also for discovering cancer cells’ vulnerability. As cancer immunotherapy to treat cancer patients and the use of metabolomics technologies become more and more common [3], the importance of the interplay between cancer cells and immune cells in the TME is emerging with respect to not only cell-to-cell interactions but also metabolic pathways. This interaction between immune cells and cancer cells is a complex and dynamic process in which immune cells act as a determinant factor of cancer cells’ fate and vice versa. In this chapter, we provide an overview of the metabolic interplay between immune cells and cancer cells and discuss the therapeutic opportunities as a result of this interplay in order to define targets for cancer treatment. It is important to understand and identify therapeutic targets that interrupt this cancerpromoting relationship between cancer cells and the surrounding immune cells, allowing for maximum efficacy of immune checkpoint inhibitors as well as other genetic and cellular therapies.

scholarly journals Crosstalk Between the Tumor Microenvironment and Cancer Cells: A Promising Predictive Biomarker for Immune Checkpoint Inhibitors

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaoying Li ◽  
Yueyao Yang ◽  
Qian Huang ◽  
Yu Deng ◽  
Fukun Guo ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Small Proportion ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarker ◽  
Cell Populations ◽  
Functional Interaction

Immune checkpoint inhibitors (ICIs) have changed the landscape of cancer treatment and are emerging as promising curative treatments in different type of cancers. However, only a small proportion of patients have benefited from ICIs and there is an urgent need to find robust biomarkers for individualized immunotherapy and to explore the causes of immunotherapy resistance. In this article, we review the roles of immune cells in the tumor microenvironment (TME) and discuss the effects of ICIs on these cell populations. We discuss the potential of the functional interaction between the TME and cancer cells as a predictive biomarker for ICIs. Furthermore, we outline the potential personalized strategies to improve the effectiveness of ICIs with precision.

scholarly journals Semaphorin Signaling in Cancer-Associated Inflammation

2019 ◽  
Vol 20 (2) ◽  
pp. 377 ◽  
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.

scholarly journals Cancer cell metabolic reprogramming: a keystone for the response to immunotherapy

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Michaël Cerezo ◽  
Stéphane Rocchi
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Metabolic Pathways ◽  
Immune Checkpoint Inhibitors ◽  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Metabolic Reprogramming ◽  
Limited Resources ◽  
Antitumor Response ◽  
Secondary Resistance

Abstract By targeting the tumor microenvironment to stimulate antitumor immunity, immunotherapies have revolutionized cancer treatment. However, many patients do not respond initially or develop secondary resistance. Based on the limited resources in the tumor microenvironment and competition between tumor and immune cells, the field of immune metabolism has produced extensive knowledge showing that targeting metabolism could help to modulate antitumor immunity. However, among all the different potentially targetable metabolic pathways, it remains unclear which have more potential to overcome resistance to immune checkpoint inhibitors. Here, we explore metabolic reprogramming in cancer cells, which might inhibit antitumor immunity, and strategies that can be used to favor the antitumor response.

scholarly journals Predictive Biomarkers of Immune Checkpoint Inhibitor Response in Breast Cancer: Looking beyond Tumoral PD-L1

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1863
Author(s):  
Nan Chen ◽  
Nicole Higashiyama ◽  
Valentina Hoyos
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Large Scale ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Predictive Biomarkers

Immune checkpoint inhibitors utilize the immune system to kill cancer cells and are now widely applied across numerous malignancies. Pembrolizumab has two breast-specific indications in triple-negative disease. Currently, programmed death ligand-1 (PD-L1) expression on tumor and surrounding immune cells is the only validated predictive biomarker for immune checkpoint inhibitors (ICIs) in breast cancer; however, it can be imprecise. Additional biomarkers are needed to identify the patient population who will derive the most benefit from these therapies. The tumor immune microenvironment contains many biomarker candidates. In tumor cells, tumor mutational burden has emerged as a robust biomarker across malignancies in general, with higher burden cancers demonstrating improved response, but will need further refinement for less mutated cancers. Preliminary studies suggest that mutations in breast cancer gene 2 (BRCA-2) are associated with increased immune infiltration and response to ICI therapy. Other genomic alterations are also being investigated as potential predictive biomarkers. In immune cells, increased quantity of tumor-infiltrating lymphocytes and CD8+ cytotoxic T cells have correlated with response to immunotherapy treatment. The role of other immune cell phenotypes is being investigated. Peripherally, many liquid-based biomarker strategies such as PD-L1 expression on circulating tumor cells and peripheral immune cell quantification are being studied; however, these strategies require further standardization and refinement prior to large-scale testing. Ultimately, multiple biomarkers utilized together may be needed to best identify the appropriate patients for these treatments.

scholarly journals The Role of Tumor Necrosis Factor in Manipulating the Immunological Response of Tumor Microenvironment

2021 ◽  
Vol 12 ◽  
Author(s):  
Dipranjan Laha ◽  
Robert Grant ◽  
Prachi Mishra ◽  
Naris Nilubol
Keyword(s):  
Drug Delivery ◽  
Extracellular Matrix ◽  
Tumor Microenvironment ◽  
Tumor Necrosis Factor ◽  
Tumor Cells ◽  
Immune Cells ◽  
Tumor Necrosis ◽  
Cancer Drug ◽  
Tnf Α ◽  
Necrosis Factor

The tumor microenvironment (TME) is an intricate system within solid neoplasms. In this review, we aim to provide an updated insight into the TME with a focus on the effects of tumor necrosis factor-α (TNF-α) on its various components and the use of TNF-α to improve the efficiency of drug delivery. The TME comprises the supporting structure of the tumor, such as its extracellular matrix and vasculature. In addition to cancer cells and cancer stem cells, the TME contains various other cell types, including pericytes, tumor-associated fibroblasts, smooth muscle cells, and immune cells. These cells produce signaling molecules such as growth factors, cytokines, hormones, and extracellular matrix proteins. This review summarizes the intricate balance between pro-oncogenic and tumor-suppressive functions that various non-tumor cells within the TME exert. We focused on the interaction between tumor cells and immune cells in the TME that plays an essential role in regulating the immune response, tumorigenesis, invasion, and metastasis. The multifunctional cytokine, TNF-α, plays essential roles in diverse cellular events within the TME. The uses of TNF-α in cancer treatment and to facilitate cancer drug delivery are discussed. The effects of TNF-α on tumor neovasculature and tumor interstitial fluid pressure that improve treatment efficacy are summarized.

scholarly journals How Phosphatidylserine Is Exposed on Tumor Cells Determines The Tumor’s Microenvironment and the Success or Failure of Checkpoint Therapy

2021 ◽  
Author(s):  
James Randall Kennedy
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
Immune Cells ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Mitotic Cell ◽  
Continuous Growth ◽  
Inflammatory Microenvironment ◽  
A Cell ◽  
Programed Cell Death

Abstract One constant in all malignant somatic tumors is their continuous growth and it is hypothesized that there are only two types of cell mutations that can cause this and that their microenvironments are determined by how those mutated cells eventually die and by how phosphatidylserine (PS) is exposed on their surface. When a mutation in a cell causes its rate of mitotic cell division to continuously exceed the rate necessary for its replacement after its programed cell death (PCD) a continuously growing tumor will form and all of the tumor cells will expose PS by the Xkr8 transmembrane scramblase molecule when they die causing an inflammatory and immune suppressive microenvironment. When a mutation in a cell eliminates PCD a continuous tumor growth begins because all those cells will continue dividing until they die a senescent death where PS is exposed by the TMEM16F scramblase molecule and causes an inflammatory microenvironment. Inflammation stresses somatic cells to expose checkpoint molecules (CPMs) on them and on immune cells that could potentially eliminate them. Only in tumors where PCD has been eliminated will CPM be exposed and only in them will immune checkpoint inhibitors (ICIs) be effective.

scholarly journals A Holistic Perspective: Exosomes Shuttle between Nerves and Immune Cells in the Tumor Microenvironment

2020 ◽  
Vol 9 (11) ◽  
pp. 3529
Author(s):  
Mihnea P. Dragomir ◽  
Vlad Moisoiu ◽  
Roxana Manaila ◽  
Barbara Pardini ◽  
Erik Knutsen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Immune Cells ◽  
Checkpoint Inhibitors ◽  
Systemic Disease ◽  
Improved Outcomes ◽  
Complex Landscape ◽  
Endothelial Growth Factor

One of the limitations of cancer research has been the restricted focus on tumor cells and the omission of other non-malignant cells that are constitutive elements of this systemic disease. Current research is focused on the bidirectional communication between tumor cells and other components of the tumor microenvironment (TME), such as immune and endothelial cells, and nerves. A major success of this bidirectional approach has been the development of immunotherapy. Recently, a more complex landscape involving a multi-lateral communication between the non-malignant components of the TME started to emerge. A prime example is the interplay between immune and endothelial cells, which led to the approval of anti-vascular endothelial growth factor-therapy combined with immune checkpoint inhibitors and classical chemotherapy in non-small cell lung cancer. Hence, a paradigm shift approach is to characterize the crosstalk between different non-malignant components of the TME and understand their role in tumorigenesis. In this perspective, we discuss the interplay between nerves and immune cells within the TME. In particular, we focus on exosomes and microRNAs as a systemic, rapid and dynamic communication channel between tumor cells, nerves and immune cells contributing to cancer progression. Finally, we discuss how combinatorial therapies blocking this tumorigenic cross-talk could lead to improved outcomes for cancer patients.

scholarly journals Current status of cancer immunotherapy with immune checkpoint inhibitors

2021 ◽  
Vol 64 (5) ◽  
pp. 326-331
Author(s):  
Myung Ah Lee
Keyword(s):  
Tumor Microenvironment ◽  
Immune Responses ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Therapeutic Agents ◽  
Chemotherapeutic Agents ◽  
Current Status ◽  
Host Immune System

The clinical outcome in advanced cancer has improved since the development of targeted therapies and immune checkpoint inhibitors. We can expect better overall survival after a combination treatment with these therapeutic agents. Classical cytotoxic chemotherapeutic agents directly kill tumor cells by destroying the cell structure and DNA of tumor cells or inhibiting their metabolism. Targeted therapy also directly affects tumor cells by inhibiting the cell growth signaling system. Conversely, immune checkpoint inhibitors can enhance immune responses by using the host immune system in the tumor microenvironment, leading to the direct killing of tumor cells. Therefore, immune checkpoint inhibitors are less toxic and have longer response durations. Even in solid tumors with nonimmunogenic backgrounds, cytotoxic chemotherapy or targeted treatment can induce immune responses to place the tumor microenvironment in an immunogenic state. Synergistic anticancer effects can be expected when immune checkpoint inhibitors are added during this state. Moreover, drug resistance may be overcome by combination therapies. If patients with cancer are treated with a combination of these therapeutic agents and the characteristics of each tumor are identified with data from next generation sequencing, personalized treatments can be tailored, making it possible to control cancers as a curable disease just like other benign chronic diseases.

scholarly journals Exosome-Mediated Crosstalk Between Tumor and Tumor-Associated Macrophages

2021 ◽  
Vol 8 ◽  
Author(s):  
Qi Chen ◽  
Yuefeng Li ◽  
Wujiang Gao ◽  
Lu Chen ◽  
Wenlin Xu ◽  
...  
Keyword(s):  
Amino Acids ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Immune Cells ◽  
Tumor Treatment ◽  
Cellular Functions ◽  
Tumor Associated Macrophages ◽  
Cancer Types ◽  
Cell Dissemination

Exosomes are nanosized vesicles, derived from the endolysosomal compartment of cells and can shuttle diverse biomolecules such as nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their origin cells. Delivery of these cargoes to recipient cells enables exosomes to influence diverse cellular functions. As one of the most abundant immune cells in the tumor microenvironment, tumor-associated macrophages (TAMs) are educated by the tumor milieu, which is rich in cancer cells and stroma components, to exert functions such as the promotion of tumor growth, immunosuppression, angiogenesis, and cancer cell dissemination. Herein, we focus on exosomes-mediated intercellular communication between tumor cells and TAM in the tumor microenvironment, which may provide new targets for anti-tumor treatment. In this review, we highlight the most recent studies on the effect of tumor/macrophage-derived exosomes on macrophage/tumor function in different cancer types.

scholarly journals Metabolic Reprogramming in the Tumor Microenvironment With Immunocytes and Immune Checkpoints

2021 ◽  
Vol 11 ◽  
Author(s):  
Yaolin Xu ◽  
Lijie He ◽  
Qiang Fu ◽  
Junzhe Hu
Keyword(s):  
Clinical Trials ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Mitochondrial Biogenesis ◽  
Immune Cells ◽  
Checkpoint Inhibitors ◽  
Tumor Therapy ◽  
Nucleotide Metabolism ◽  
Metabolic Reprogramming ◽  
Immune Checkpoints

Immune checkpoint inhibitors (ICIs), Ipilimumab, Nivolumab, Pembrolizumab and Atezolizumab, have been applied in anti-tumor therapy and demonstrated exciting performance compared to conventional treatments. However, the unsatisfactory response rates, high recurrence and adaptive resistance limit their benefits. Metabolic reprogramming appears to be one of the crucial barriers to immunotherapy. The deprivation of required nutrients and altered metabolites not only promote tumor progression but also confer dysfunction on immune cells in the tumor microenvironment (TME). Glycolysis plays a central role in metabolic reprogramming and immunoregulation in the TME, and many therapies targeting glycolysis have been developed, and their combinations with ICIs are in preclinical and clinical trials. Additional attention has been paid to the role of amino acids, lipids, nucleotides and mitochondrial biogenesis in metabolic reprogramming and clinical anti-tumor therapy. This review attempts to describe reprogramming metabolisms within tumor cells and immune cells, from the aspects of glycolysis, amino acid metabolism, lipid metabolism, nucleotide metabolism and mitochondrial biogenesis and their impact on immunity in the TME, as well as the significance of targeting metabolism in anti-tumor therapy, especially in combination with ICIs. In particular, we highlight the expression mechanism of programmed cell death (ligand) 1 [PD-(L)1] in tumor cells and immune cells under reprogramming metabolism, and discuss in detail the potential of targeting key metabolic pathways to break resistance and improve the efficacy of ICIs based on results from current preclinical and clinical trials. Besides, we draw out biomarkers of potential predictive value in ICIs treatment from a metabolic perspective.

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