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Modified Hypoxia-Inducible Factor Expression in CD8+ T Cells Increases Antitumor Efficacy
Pedro Veliça1, Pedro P Cunha1,2, Nikola Vojnovic1
1Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
Cancer Immunology Research
|February 19, 2021
Summary
Enhancing adoptive cell therapy, researchers found that manipulating hypoxia-inducible factor 2-alpha (HIF2α) significantly boosts cytotoxic T cell survival and anti-tumor function. This modification improves cancer immunotherapy effectiveness.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- Adoptive cell therapy (ACT) using cytotoxic T cells is a promising cancer immunotherapy.
- Enhancing the survival and function of transferred T cells is crucial for ACT efficacy.
- Solid tumors' hypoxic microenvironment presents a challenge for T cell adaptation and survival.
Purpose of the Study:
- To identify structural features of hypoxia-inducible factor (HIF) that enhance antitumor T cell efficacy.
- To investigate the role of HIF1α and HIF2α in CD8+ T cell adaptation and function within tumor microenvironments.
- To develop strategies for improving the therapeutic potential of engineered T cells.
Main Methods:
- Retroviral vectors were used to express HIF1α and HIF2α in mouse CD8+ T cells, with varying sensitivity to HIF inhibitors.
- Engineered T cells were assessed for transcriptional changes, cytotoxic differentiation, and cytolytic activity against tumor targets.
- An FIH-insensitive HIF2α mutant was tested in combination with a chimeric antigen receptor (CAR) in human T cells for anti-lymphoma activity.
Main Results:
- HIF2α expression, unlike HIF1α, induced significant transcriptional reprogramming in CD8+ T cells, enhancing cytotoxic differentiation and function.
- A specific mutation rendering HIF2α insensitive to factor-inhibiting HIF (FIH) resulted in highly effective antitumor T cells post-adoptive transfer.
- Co-expression of FIH-insensitive HIF2α with an anti-CD19 CAR markedly improved human T cell killing of lymphoma cells in vitro and in vivo.
Conclusions:
- Ectopic expression of HIF transcription factors, particularly a modified HIF2α, can significantly enhance the antitumor efficacy of therapeutic CD8+ T cells.
- Targeting HIF pathways offers a viable strategy to improve the persistence and functionality of T cells in cancer immunotherapy.
- These findings provide a foundation for engineering more potent cell-based cancer therapies.
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