Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy

Cunha, P. P.; Minogue, E.; Krause, L. C.; Hess, R. M.; Bargiela, D.; Wadsworth, B. J.; Barbieri, L.; Brombach, C.; Foskolou, I. P.; Bogeski, I.; Velica, P.; Johnson, R.

doi:10.1101/2022.11.25.517976

bioRxiv · 10.1101/2022.11.25.517976

Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy

Cunha, P. P.·Minogue, E.·Krause, L. C.·Hess, R. M.·Bargiela, D.·Wadsworth, B. J.·Barbieri, L.·Brombach, C.·Foskolou, I. P.·Bogeski, I.·Velica, P.·Johnson, R.

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Abstract

SummaryOxygenation levels are a determinative factor in T cell function. Here we describe that the oxygen tensions sensed by 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 hours 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.

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Cunha, P. P., Minogue, E., Krause, L. C., Hess, R. M., Bargiela, D., Wadsworth, B. J., Barbieri, L., Brombach, C., Foskolou, I. P., Bogeski, I., Velica, P., Johnson, R.. 2022-11-27. Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy. https://doi.org/10.1101/2022.11.25.517976

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