Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy
Pedro P. Cunha, Eleanor Minogue, Lena C.M. Krause, Rita M. Hess, David Bargiela, Brennan J. Wadsworth, Laura Barbieri, Carolin Brombach, Iosifina P. Foskolou, Ivan Bogeski, Pedro Veliça, Randall S. Johnson
Abstract
Oxygenation levels are a determinative factor in T cell function. Here, we describe how oxygen tensions sensed by mouse and human T cells at the moment of activation act to persistently modulate both differentiation and function. We found that in a protocol of CAR-T cell generation, 24 hr of low oxygen levels during initial CD8 + T cell priming is sufficient to enhance antitumour cytotoxicity in a preclinical model. This is the case even when CAR-T cells are subsequently cultured under high oxygen tensions prior to adoptive transfer. Increased hypoxia-inducible transcription factor (HIF) expression was able to alter T cell fate in a similar manner to exposure to low oxygen tensions; however, only a controlled or temporary increase in HIF signalling was able to consistently improve cytotoxic function of T cells. These data show that oxygenation levels during and immediately after T cell activation play an essential role in regulating T cell function.