Abstract
Simple SummaryIn a tumor context, antitumor immune cells mediate an inflammatory response after activating a metabolic switch to kill cancer cells. However, tumors develop strategies to avoid destruction. Cancer cells are able to modify the metabolic environment of the tumor by sequestering nutrients (e.g., glucose, tryptophan, arginine) and by producing toxic waste compounds (e.g., adenosine, lactate, kynurenine). This tumor environment promotes exhaustion of antitumor immune cells while driving the expansion of Tregs and the expression of immune checkpoints. Establishment of such an immunosuppressive tumor environment decreases treatment response of cancer patients to immunotherapy. Interestingly, immunometabolism knowledge allows new therapeutic strategies to increase antitumor immune response by targeting the metabolism of both cancer and immune cells to improve immunotherapy.Over the past decade, advances in cancer immunotherapy through PD1–PDL1 and CTLA4 immune checkpoint blockade have revolutionized the management of cancer treatment. However, these treatments are inefficient for many cancers, and unfortunately, few patients respond to these treatments. Indeed, altered metabolic pathways in the tumor play a pivotal role in tumor growth and immune response. Thus, the immunosuppressive tumor microenvironment (TME) reprograms the behavior of immune cells by altering their cellular machinery and nutrient availability to limit antitumor functions. Today, thanks to a better understanding of cancer metabolism, immunometabolism and immune checkpoint evasion, the development of new therapeutic approaches targeting the energy metabolism of cancer or immune cells greatly improve the efficacy of immunotherapy in different cancer models. Herein, we highlight the changes in metabolic pathways that regulate the differentiation of pro- and antitumor immune cells and how TME-induced metabolic stress impedes their antitumor activity. Finally, we propose some drug strategies to target these pathways in the context of cancer immunotherapy.
Highlights
Thanks to a renewed interest in the last decade, tumor metabolism is well characterized [1]
Amino acids or fatty acids are metabolized through glycolysis and/or the tricarboxylic acid (TCA) cycle to be converted into adenosine triphosphate (ATP), proteins, lipids and lactate to support the energy and “building block” demands of highly proliferative cells [4,5,6]
The metabolic deregulation and competition created by cancer cells in the tumor microenvironment (TME) disrupt their differentiation and alter many parameters such as their fitness, polarization, recruitment and survival
Summary
Thanks to a renewed interest in the last decade, tumor metabolism is well characterized [1]. The “hallmarks of cancer” were updated in 2011 by Hanahan and Weinberg to include cancer metabolic reprogramming and immune escape in the definition of cancer progression This has created a new impetus for research into immunotherapy and the metabolic crosstalk between immune and tumor cells [1]. Immune escape is promoted by hypoxia, glucose depletion and toxic waste product (e.g., lactate and kynurenine) enrichment in the TME [10,11,16] All these environmental conditions cause inhibition of tumor antigen presentation by APCs and a decrease in the fitness of all antitumor immune cells (e.g., T effector, NK, M1), whereas protumor immune cells (Treg, M2 and MDSC) proliferate and expression of inhibitory checkpoint ligands (e.g., PD1) increases on the surface of immune cells to inhibit antitumor immunity [11,17]. We provide some innovative therapeutic strategies using key metabolic targets to reprogram immune cell metabolism to improve immunotherapies
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