Modified Hypoxia-Inducible Factor Expression in CD8+ T Cells Increases Antitumor Efficacy
- 18 February 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Immunology Research
- Vol. 9 (4), 401-414
- https://doi.org/10.1158/2326-6066.cir-20-0561
Abstract
Adoptive transfer of antitumor cytotoxic T cells is an emerging form of cancer immunotherapy. A key challenge to expanding the utility of adoptive cell therapies is how to enhance the survival and function of the transferred T cells. Immune-cell survival requires adaptation to different microenvironments and particularly to the hypoxic milieu of solid tumors. The hypoxia-inducible factor (HIF) transcription factors are an essential aspect of this adaptation. In this study, we undertook experiments to define structural determinants of HIF that potentiate antitumor efficacy in cytotoxic T cells. We first created retroviral vectors to deliver ectopic expression of HIF1α and HIF2α in mouse CD8+ T cells, together or individually and with or without sensitivity to the oxygen-dependent HIFα inhibitors Von Hippel–Lindau and factor-inhibiting HIF (FIH). HIF2α, but not HIF1α, drove broad transcriptional changes in CD8+ T cells, resulting in increased cytotoxic differentiation and cytolytic function against tumor targets. A specific mutation replacing the hydroxyl group–acceptor site for FIH in HIF2α gave rise to the most effective antitumor T cells after adoptive transfer in vivo. In addition, codelivering an FIH-insensitive form of HIF2α with an anti-CD19 chimeric antigen receptor greatly enhanced cytolytic function of human CD8+ T cells against lymphoma cells both in vitro and in a xenograft adoptive transfer model. These experiments point to a means to increase the antitumor efficacy of therapeutic CD8+ T cells via ectopic expression of the HIF transcription factor. See related Spotlight on p. 364Keywords
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Funding Information
- Swedish Cancer Society (CAN2018/808)
- Swedish Childhood Cancer Foundation (PR2020-0075)
- Swedish Research Council (2019-01485)
- Wellcome Trust (214283/Z/18/Z)
- Portuguese Foundation for Science and Technology (SFRH/BD/115612/2016)
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