Immune checkpoint blockades, or ICBs, have revolutionized treatment for various advanced cancers. However, their effectiveness has plateaued due to therapeutic resistance that renders tumor-infiltrating lymphocytes, or TILs, ineffective.
University of Alabama at BirminghamDec 14 2024 Thus, finding ways to disarm that resistance and rejuvenate anti-cancer TILs -; so they can kill tumor cells -; is an important goal for cancer clinicians. Yet any potential intervention has to take place under unusual conditions -; the cancer microenvironment nearly devoid of oxygen due to fast growth of a tumor and the poor oxygen delivery by the abnormal tumor vasculature.
The UAB researchers found that HIF1α-glycolysis is indispensable for IFN-γ induction in hypoxic T cells. HIF1α is a subunit of HIF, or hypoxia-inducible factor, that is known to play a crucial role in orchestrating cellular responses to hypoxia. With regard to defense against cancer, the researchers found that hypoxic T cells deleted for HIF1α were less able to kill tumor cells in vitro. In vivo, tumor-bearing mice that had the HIF1α-deleted in T cells did not respond to ICB therapy.
TILs and tumor cells utilize the same metabolic pathways for their growth and function, and co-live in the metabolically harsh tumor-microenvironments characterized by hypoxia and poor nutrition, placing them in a fierce metabolic tug-of-war. How to tilt this metabolic battle to favor TILs would be key, and we showed that acetate supplementation restored IFN-γ production in Hif1α-deletion-TILs and overcame ICB resistance derived from HIF1α loss in T cells.
Hypoxia Cell Cell Death Cytokine Glycolysis Interferon Intracellular Metabolism Oncology Oxygen Ph Pharmacology Research Toxicology Tumor Vasculature
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