Hypoxia Supports Differentiation of Terminally Exhausted CD8 T Cells

Abstract

Hypoxia, angiogenesis, and immunosuppression have been proposed to be interrelated events that fuel tumor progression and impair the clinical effectiveness of anti-tumor therapies. Here we present new mechanistic data highlighting the role of hypoxia in fine-tuning CD8 T cell exhaustion in vitro, in an attempt to reconcile seemingly opposite evidence regarding the impact of hypoxia on functional features of exhausted CD8 T cells. Focusing on the recently characterized terminally-differentiated and progenitor exhausted CD8 T cells, we found that both hypoxia and its regulated mediator, vascular endothelial growth factor (VEGF)-A, promote the differentiation of PD-1+ TIM-3+ CXCR5+ terminally exhausted-like CD8 T cells at the expense of PD-1+ TIM-3- progenitor-like subsets without affecting tumor necrosis factor (TNF)-α and interferon (IFN)-γ production or granzyme B (GZMB) expression by these subpopulations. Interestingly, hypoxia accentuated the proangiogenic secretory profile in exhausted CD8 T cells. VEGF-A was the main factor differentially secreted by exhausted CD8 T cells under hypoxic conditions. In this sense, we found that VEGF-A contributes to generation of terminally exhausted CD8 T cells during in vitro differentiation. Altogether, our findings highlight the reciprocal regulation between hypoxia, angiogenesis, and immunosuppression, providing a rational basis to optimize synergistic combinations of antiangiogenic and immunotherapeutic strategies, with the overarching goal of improving the efficacy of these treatments.

Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer

“…Recently, exhausted T cells were further categorized into progenitor exhausted T cells and terminally exhausted T cells, as defined as PD1+TIM3-TCF1+ and PD1+TIM3+TCF1- T cells respectively [ 71 ]. Interestingly, it has been recently shown that hypoxia drove the differentiation of mouse progenitor exhausted T cells to terminally exhausted T cells in vitro [ 72 ]. While these two subsets of exhausted T cells await further characterization in HCC, another emerging question that merits further exploration is whether hypoxia drives exhausted T cell differentiation through HIF-mediated transcription of genes or hypoxia-induced metabolites in T cells.…”

Unraveling How Tumor-Derived Galectins Contribute to Anti-Cancer Immunity Failure

“…Tumor-induced hypoxia is a major driving force that promotes angiogenesis and impairs effector immune responses [ 345 , 346 ]. Indeed, in vitro studies have demonstrated that hypoxia promotes the differentiation of PD-1+ Tim-3+ terminally exhausted-like CD8+ T cells [ 347 ]. Furthermore, these exhausted T cells are resistant to inhibitory checkpoints strategies [ 348 ].…”

(Im)maturity in Tumor Ecosystem

“…This is an outcome of an in vitro study by Bannoud and colleagues. Terminally exhausted T cells due to representing a terminal differentiation position do not recover their effector functionality using ICIs ( 118 ).…”