Metabolic Regulation of CAR T Cell Function by the Hypoxic Microenvironment in Solid Tumors

Abstract

The field of immunometabolism has attracted growing attention as an area at the heart of immune regulation. Upon activation, T cells undergo significant metabolic changes allowing them to mediate effector responses. The advent of chimeric antigen receptor T cell-adoptive therapy has shown some striking clinical efficacy but fails to induce sufficient antitumor response in many patients. Solid tumors put up significant opposition creating a microenvironment deficient of oxygen and glucose, depriving T cells of energy and pushing them to exhaustion. Here, we focus on immune suppressive mechanisms related to hypoxia in the tumor microenvironment and the resulting metabolic changes in T cells. New therapeutic approaches such as generating chimeric antigen receptor T cells able to withstand the challenging solid tumor microenvironment are needed.

Preclinical Activity of Embryonic Annexin A2-Specific Chimeric Antigen Receptor T Cells Against Ovarian Cancer

“…In addition, the hostile tumour microenvironment is likely to be more challenging to treat than the xenograft model used here as proof-of-concept. Immunosuppressory cells, immune checkpoint molecules, and immunosuppressive cytokines all contribute to limiting the efficacy of CAR T cells in solid tumours [33].…”

T cell metabolism in chronic viral infection

“…The most prominent metabolic deficiency described in exhausted T cells is mitochondrial dysfunction (Fig. 1c), which may result directly from environmental stresses such as hypoxia and nutrient deprivation and/or an excess of co-inhibitory signalling [68]. Changes to mitochondrial function can already be observed early during the establishment of murine LCMV persistency [63] and are maintained in long-term chronic viral infection [40,69] -a situation that is also observed in cancer [67].…”

Editor's Pick: Tumour-Associated Hypoxia: Can We Give Chimeric Antigen Receptor T Cells More Breathing Space?

“…Hypoxia refers to a low concentration of oxygen and is a frequent attribute of solid tumours. 18 It commonly results from rapid tumour growth that outstrips an inadequate and often abnormal blood supply. Hypoxia has been associated with tumour cell invasiveness, metastasis, epithelial to mesenchymal transition, maintenance of cancer stem cells, and resistance to both radiation and cytotoxic chemotherapy.…”