The role of tumor metabolism in modulating T-Cell activity and in optimizing immunotherapy

Abstract

Immunotherapy has revolutionized cancer treatment and revitalized efforts to harness the power of the immune system to combat a variety of cancer types more effectively. However, low clinical response rates and differences in outcomes due to variations in the immune landscape among patients with cancer continue to be major limitations to immunotherapy. Recent efforts to improve responses to immunotherapy have focused on targeting cellular metabolism, as the metabolic characteristics of cancer cells can directly influence the activity and metabolism of immune cells, particularly T cells. Although the metabolic pathways of various cancer cells and T cells have been extensively reviewed, the intersections among these pathways, and their potential use as targets for improving responses to immune-checkpoint blockade therapies, are not completely understood. This review focuses on the interplay between tumor metabolites and T-cell dysfunction as well as the relationship between several T-cell metabolic patterns and T-cell activity/function in tumor immunology. Understanding these relationships could offer new avenues for improving responses to immunotherapy on a metabolic basis.

Keywords: T cell; cancer; immunotherapy; metabolism; tumor immune microenvironment.

Figure 1

Key regulatory effects and interactions between tumor metabolic pathways and T-cell activity. Aerobic glycolysis in tumors is primarily responsible for creating a hypoxic, acidic, and nutrient-depleted microenvironment that suppresses effector T-cell activity and blunts antitumor immune responses. Similarly, the rapid uptake and catabolism of amino acids by tumors reduces their availability for T cells, which further promotes immunosuppression and supports the metabolic activities of regulatory T cells as opposed to effector T cells. Tumors can upregulate both fatty acid oxidation (FAO) and fatty acid synthesis (FAS), which affect T-cell activity differently. The accumulation of select fatty acids can support FAO in T cells; however, those same fatty acids can also promote exhaustion and inhibit the proliferation of memory T cells. Cholesterol is particularly significant for causing mitochondrial and endoplasmic reticulum (ER) stress in T cells. Red arrows and text indicate tumor metabolism–mediated effects that can suppress antitumor T-cell activity. Green arrows and text indicate tumor metabolism–mediated effects that can support antitumor T-cell activity. AA, amino acid; Arg, arginine; ER, endoplasmic reticulum; FA, fatty acid; FAO, fatty acid oxidation; FAS, fatty acid synthesis; Gln, glutamine; PD1, programmed cell death protein 1; T_reg, regulatory T cell; T_eff, effector T cell; TCR, T-cell receptor; Trp, tryptophan.