Hypoxia and antitumor CD8⁺ T cells: An incompatible alliance?

Abstract

T Lymphocytes face pathologically low O2 tensions within the tumor bed at which they will have to function in order to impact on the malignancy. Recent studies highlighting the importance of O2 and hypoxia-inducible factors for CD8+ T-cell function and fate must now be integrated into tumor immunology concepts if immunotherapies are to progress. Here, we discuss, reinterpret, and reconcile the many apparent contradictions in these data and we propose that O2 is a master regulator of the CD8+ T-cell response. Certain T cell functions are enhanced, others suppressed, but on balance, hypoxia is globally detrimental to the antitumor response.

Similarities and Distinctions of Cancer and Immune Metabolism in Inflammation and Tumors

“…The impact of hypoxia on CD8 T cells has been controversial. CD8 T cells were shown to have reduced proliferation and cytokine secretion at low oxygen, their cytolytic capacity was higher compared to normoxia, while other studies supported the conclusion that hypoxia is detrimental to CD8 T cell function (Caldwell et al, 2001; Vuillefroy de Silly et al, 2016). In vivo findings with T cell activation in hypoxic, normoxic and hyperoxic conditions revealed that T cell activation increased with increasing oxygen saturation, and was highest in T cells exposed to more oxygenated environments (Ohta et al, 2011).…”

Metabolic Instruction of Immunity

“…Hypoxia also has considerable effects on TIL function, proliferation, and migration (Vuillefroy de Silly et al, 2016). Increases in HIF-1α activity by culturing T cells in physiologic normoxia (~3–5% O 2 ), genetic deletion of von Hippel-Lindau (VHL) factor, or inhibiting activity of the oxygen-sensing prolyl-hydroxylase (PHD) family of proteins, enhances CD8 T cell glycolysis and effector functions and promotes antitumor immunity (Clever et al, 2016; Doedens et al, 2013; Finlay et al, 2012; Wang et al, 2011).…”

Sculpting tumor microenvironment with immune system: from immunometabolism to immunoediting

“…TCR activation also induces mitochondrial biogenesis and fission, leading to looser cristae structures and lower respiratory functions [38]. In addition to glucose deprivation, hypoxia, which is another physiological factor in the immunosuppressive TME, also has considerable impacts on TIL proliferation and function [24]. In support of this, several studies have demonstrated that increasing glucose consumption REVIEW SERIES: TRANSLATING IMMUNOMETABOLISM via up-regulated glycolysis activity in cancer cells indeed represses glucose uptake and utilization in tumor-infiltrating lymphocytes (TILs), thereby impeding anti-tumor immunity [32,33].…”

“…Among these cancer immunotherapies, immune check-point blockade (ICB), that blocks inhibitory receptors such as cytotoxic T lymphocyte antigen (CTLA)-4 and PD-1, has resulted in tremendous success in the treatments of several types of cancer by rejuvenating dysfunctional tumor-specific T cells. In addition to the immune check-points, the immunomodulatory cells and immunosuppressive molecules, physiological changes in TME, such as hypoxia, low pH, nutrient deprivation and production of immunosuppressive metabolites, could also impede anti-tumor immunity [22][23][24][25][26]. Several strategies targeting prostaglandin E 2 , cytokines and indoleamine 2,3-dioxygenase (IDO) have been also developed to alleviate immunosuppressive traits in the TME and further improve T cell immunity and tumor control [19][20][21].…”