Abstract

Immunotherapy has changed the treatment paradigm in multiple solid and hematologic malignancies. However, response remains limited in a significant number of cases, with tumors developing innate or acquired resistance to checkpoint inhibition. Certain “hot” or “immune-sensitive” tumors become “cold” or “immune-resistant”, with resultant tumor growth and disease progression. Multiple factors are at play both at the cellular and host levels. The tumor microenvironment (TME) contributes the most to immune-resistance, with nutrient deficiency, hypoxia, acidity and different secreted inflammatory markers, all contributing to modulation of immune-metabolism and reprogramming of immune cells towards pro- or anti-inflammatory phenotypes. Both the tumor and surrounding immune cells require high amounts of glucose, amino acids and fatty acids to fulfill their energy demands. Thus, both compete over one pool of nutrients that falls short on needs, obliging cells to resort to alternative adaptive metabolic mechanisms that take part in shaping their inflammatory phenotypes. Aerobic or anaerobic glycolysis, oxidative phosphorylation, tryptophan catabolism, glutaminolysis, fatty acid synthesis or fatty acid oxidation, etc. are all mechanisms that contribute to immune modulation. Different pathways are triggered leading to genetic and epigenetic modulation with consequent reprogramming of immune cells such as T-cells (effector, memory or regulatory), tumor-associated macrophages (TAMs) (M1 or M2), natural killers (NK) cells (active or senescent), and dendritic cells (DC) (effector or tolerogenic), etc. Even host factors such as inflammatory conditions, obesity, caloric deficit, gender, infections, microbiota and smoking status, may be as well contributory to immune modulation, anti-tumor immunity and response to immune checkpoint inhibition. Given the complex and delicate metabolic networks within the tumor microenvironment controlling immune response, targeting key metabolic modulators may represent a valid therapeutic option to be combined with checkpoint inhibitors in an attempt to regain immune function.

Highlights

  • The introduction of immunotherapy to the treatment algorithms of malignant diseases has revolutionized the field of oncology with attention being shifted from off-target bombardment of tumor cells by using standard chemotherapy, to focused immune enhancement against tumor cells using vaccines, cytokines, adoptive cell therapy (ACT) and checkpoint inhibition

  • We provide and insight towardstothe inter-dependent immune-metabolic drivers of immunosuppression resistance immunotherapy, checkpoint drivers of immunosuppression and resistance to immunotherapy, checkpoint inhibition, both at the cellular level, within the tumor microenvironment (TME), and at the host level, causing

  • L-arginine metabolism in macrophages leads to nitric oxide (NO) production using the inducible NO synthase, which eventually leads to the suppression of enzymes needed in TCA-electron transport chain (ETC) pathways, and promotes glycolysis as well as M1 phenotype transformation

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Summary

Introduction

The introduction of immunotherapy to the treatment algorithms of malignant diseases has revolutionized the field of oncology with attention being shifted from off-target bombardment of tumor cells by using standard chemotherapy, to focused immune enhancement against tumor cells using vaccines, cytokines, adoptive cell therapy (ACT) and checkpoint inhibition. (PD-1), and programmed cell-death protein ligand-1 (PDL-1) [1] These inhibitory checkpoints impede the immune response and induce tolerance, thereby regulating the immunity to avoid excessive activation against one’s self through auto-reactivity. These inhibitory checkpoints are harnessed by tumor cells as a means for immune evasion [2]. Impact tumor response to immunotherapy but their role in antitumor immunity is uncertain Others These metabolic adaptive mechanisms, along with involved inflammatory mediators, have a major influence on ICI resistance at the cellular level via drastic alteration of immune-cell crosstalk, leading to impairment of effector T-cell activation, and stimulation of regulatory immune cells such as regulatory T-cells (T-regs), TAMs, myeloid-derived suppressor cells (MDSCs), and tolerogenic DCs, etc.

Nutrients Affecting the Cellular Activity of Immune Cells in the
Warburg
Amino-Acid Metabolism
Lipid and Fatty Acid Metabolism
Mechanisms and Pathways Modulating Metabolism and Affecting Cellular Activity
Pyruvate Kinase Muscle Splicing
Lactic Acidosis
Concept of Extracellular Vesicles
Role of Sphingosine Kinase-1
Effect of Acetyl-CoA Carboxylase
Role of MUC-1 Mucin
Effect
Cytokine
Obesity and Metabolic Syndrome
Caloric Deficit
Gender Effect
Infection
Microbiota
Smoking
Metabolic Manipulation at the Genetic and Pharmacologic Levels
Conclusions
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