| First Author | Veliça P | Year | 2021 |
| Journal | Cancer Immunol Res | Volume | 9 |
| Issue | 4 | Pages | 401-414 |
| PubMed ID | 33602720 | Mgi Jnum | J:352745 |
| Mgi Id | MGI:7661001 | Doi | 10.1158/2326-6066.CIR-20-0561 |
| Citation | Velica P, et al. (2021) Modified Hypoxia-Inducible Factor Expression in CD8(+) T Cells Increases Antitumor Efficacy. Cancer Immunol Res 9(4):401-414 |
| abstractText | 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 HIF1alpha and HIF2alpha in mouse CD8(+) T cells, together or individually and with or without sensitivity to the oxygen-dependent HIFalpha inhibitors Von Hippel-Lindau and factor-inhibiting HIF (FIH). HIF2alpha, but not HIF1alpha, 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 HIF2alpha gave rise to the most effective antitumor T cells after adoptive transfer in vivo In addition, codelivering an FIH-insensitive form of HIF2alpha 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. 364. |
