Hypoxia-inducible factor activity promotes antitumor effector function and tissue residency by CD8+ T cells

Area of Science:

• Immunology
• Cancer Biology
• Cellular Therapy

Background:

• Adoptive T cell therapies (ACTs) show promise for cancer treatment but face challenges with low response rates in solid tumors.
• Enhancing tumor-infiltrating lymphocyte (TIL) function by promoting CD8+ T cell tissue residency is a potential strategy to improve efficacy.
• The role of hypoxia-inducible factors (HIFs) in TIL function and tissue residency requires further investigation.

Purpose of the Study:

• To investigate the impact of von Hippel-Lindau (VHL) gene deletion on CD8+ T cell differentiation and function within solid tumors.
• To determine if VHL deficiency promotes a tissue-resident memory-like (Trm-like) phenotype in TILs.
• To evaluate the therapeutic potential of VHL-deficient T cells, including chimeric antigen receptor (CAR) T cells, in enhancing anti-tumor immunity.

Main Methods:

• Deletion of the VHL gene in CD8+ T cells from mouse models of malignancy.
• Analysis of TIL phenotype, including Trm signature and exhaustion markers.
• Assessment of TIL polyfunctionality, tumor accumulation, and response to αPD-1 immunotherapy.
• Evaluation of VHL deficiency in enhancing CAR T cell accumulation and phenotype in tumors.

Main Results:

• VHL deletion in CD8+ T cells induced HIF-1α/HIF-2α-dependent differentiation of Trm-like TILs.
• VHL-deficient TILs accumulated in tumors, displayed a Trm signature, and retained polyfunctionality despite an exhaustion phenotype.
• VHL deficiency led to improved response to αPD-1 immunotherapy, resulting in tumor eradication and protective memory.
• VHL deficiency enhanced the accumulation of CAR T cells with a Trm-like phenotype in tumors.

Conclusions:

• HIF activity, regulated by VHL, is crucial for promoting CD8+ TIL accumulation and anti-tumor activity.
• Targeting VHL and HIF pathways offers a novel strategy to enhance the efficacy of ACTs for solid tumors.
• Inducing a Trm-like phenotype in TILs via VHL deletion improves their persistence, polyfunctionality, and therapeutic outcomes.