Modified Hypoxia-Inducible Factor Expression in CD8+ T Cells Increases Antitumor Efficacy
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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. 364
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Other studies supported the hypothesis that HIF activity was required in a cell-autonomous manner for the antitumor activity of CD8+ T cells.
“other studies supported the hypothesis that HIF activity was required in a cell-autonomous manner for the antitumor activity of CD8+ T cells (39, 40).”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [40]
Ectopic HIF1α overexpression in mouse T cells diminishes antitumor activity in an adoptive-transfer model.
“A recent study has shown that ectopic HIF1α overexpression in mouse T cells diminished the antitumor activity in an adoptive-transfer model50.”
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Deficiency of factor-inhibiting HIF creates a tumor-promoting immune microenvironment
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“A recent study showed that in an adaptive T cell therapy setting, exogenously expressed FIH - insensitive HIF2 α increases antitumor properties of CD8 T cells (60).”
Infiltration of Tumors Is Regulated by T cell–Intrinsic Nitric Oxide Synthesis
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Targeting metabolic pathway enhance CAR-T potency for solid tumor
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“…results revealed that PDOs can be divided into NK cell-susceptible PDOs by MICA/B high and death receptor (FAS/TRAIL-R2) high expression, as well as NK cell-resistant PDOs by MHC class I high expression, and highlights the potential of our NK cell/PDO platform for the testing of therapeutic mAbs.”
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“Expression of a HIF2a mutant resistant to Factor Inhibiting HIF (FIH)-mediated suppression enhanced T cell responsiveness in the hypoxic TME (blue) (66).”
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HIF1α or HIF2α: Enhancing CD8+ T-cell Fitness for Antitumor Immunity
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“To elucidate the distinct roles of HIF1a and HIF2a and their susceptibility to oxygen regulation by PHD- versus FIH-dependent mechanisms in influencing CD8þ T-cell cytotoxicity in vitro and antitumor efficacy in vivo, Veliça and colleagues (3) compared CD8þ T cells expressing wild-type and mutant versions (resistant t…”
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“…adhesion, hypoxia that has been shown to selectively alter the expression of integrins that bind to collagen (ITG α 1, ITG α 11, ITG β 1), fibronectin (ITG α 5, ITG β 1) or hemoglobin (novel ITG α D β 1) via HIF-1 and HIF-2 signaling (Ju et al., 2017; Koivunen et al., 2025; Velica et al., 2021).”
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- Authors
- Veliça, P., Cunha, P. P., Vojnovic, N., Foskolou, I. P., Bargiela, D., Gojkovic, M., Rundqvist, H., & Johnson, R. S.
- Affiliations
- Karolinska Institutet (SE)
- University of Cambridge (GB)
- 1Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
- Corresponding author
- Johnson, Randall S.
- ORCID
- Venue
- Cancer Immunology Research
- Published
- 2021-02-18
- Volume
- 9
- Issue
- 4
- Pages
- 401-414
- ISSN
- 2326-6066 (ISSN-L)
- 2326-6074
- PMC
- PMC7611205
- OpenAlex
- W3132765763
- Cited by
- 52
- References
- 38
- Citations by year
- 2026: 2 · 2025: 13 · 2024: 12 · 2023: 8 · 2022: 12 · 2021: 5
- FWCI
- 3.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Immunology Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- 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)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- hypoxia-inducible factor, HIF-2α, HIF-1α, CD8+ T cells, adoptive T cell therapy, tumor hypoxia, cytotoxic T lymphocytes, VHL, factor inhibiting HIF, chimeric antigen receptor, anti-CD19, lymphoma, retroviral gene transfer, antitumor immunity
- MeSH terms
- Animals, Hypoxia, Female, Humans, Male, Mice, Inbred C57BL, Transcription Factors, Immunotherapy, Adoptive, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Tumor Microenvironment
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