Scanning electron micrograph of a human T lymphocyte (additionally known as a T cell) from the immune system of a wholesome donor. Credit score: NIAID
Immune checkpoint blockades, or ICBs, have revolutionized remedy for varied superior cancers. Nonetheless, their effectiveness has plateaued as a consequence of therapeutic resistance that renders tumor-infiltrating lymphocytes, or TILs, ineffective. Thus, discovering methods to disarm that resistance and rejuvenate anti-cancer TILs—to allow them to kill tumor cells—is a crucial aim for most cancers clinicians. But any potential intervention has to happen beneath uncommon situations—the most cancers microenvironment almost devoid of oxygen as a consequence of quick development of a tumor and the poor oxygen supply by the irregular tumor vasculature.
In a examine revealed in Nature Communications, Lewis Zhichang Shi, M.D., Ph.D., and College of Alabama at Birmingham colleagues present, for the primary time, how HIF1α in T cells is essential for induction of interferon gamma, or IFN-γ, in that hypoxic setting. The cytokine IFN-γ is understood to be important to induce the tumor-killing capability of T cells. Moreover, an alternate metabolism known as glycolysis, which is ready to produce vitality in human cells when no oxygen is current, is equally recognized to be required for IFN-γ induction in T cells.
“Intriguingly, under normal oxygen levels in the body, called normoxia, IFN-g induction and glycolysis in T cells are not mediated by HIF1α, a primary regulator of glycolysis, but by its widely regarded downstream target LDHa, as reported in an early study by another group,” stated Shi, a professor within the UAB Division of Radiation Oncology. “However, it has been unknown, under hypoxia, whether and how HIF1α regulates IFN-γ induction and glycolysis in T cells.”
The UAB researchers discovered that HIF1α-glycolysis is indispensable for IFN-γ induction in hypoxic T cells. HIF1α is a subunit of HIF, or hypoxia-inducible issue, that’s recognized to play a vital function in orchestrating mobile responses to hypoxia.
Shi and colleagues confirmed this key function for HIF1α in hypoxia by combining genetic mouse fashions, metabolic flux evaluation utilizing 13C-labeled glucose tracing assays and a Seahorse analyzer, in addition to pharmacological approaches.
In each human and mouse T cells that had been activated beneath hypoxia, they discovered that the deletion of HIF1α from the T cells prevented the metabolic reprogramming shift from catabolic metabolism to anabolic metabolism, of which anaerobic glycolysis is a significant part; the deletion additionally suppressed the induction of IFN-γ. Moreover, pharmacologic inhibition of T cell glycolysis beneath hypoxia prevented induction of IFN-γ. Conversely, stabilization of HIF1α by knocking out a detrimental regulator of HIF1α elevated IFN-γ beneath hypoxic situations.
With regard to protection towards most cancers, the researchers discovered that hypoxic T cells deleted for HIF1α had been much less capable of kill tumor cells in vitro. In vivo, tumor-bearing mice that had the HIF1α-deleted in T cells didn’t reply to ICB remedy.
The researchers then confirmed a technique to overcome that resistance to ICB remedy. Elucidation of the mechanistic operate of the HIF1α deletion confirmed that lack of HIF1α tremendously diminished glycolytic exercise in hypoxic T cells, leading to depleted intracellular acetyl-CoA and attenuated activation-induced cell loss of life, or AICD. Restoration of intracellular acetyl-CoA by supplementing development media with acetate reengaged AICD and rescued IFN-γ manufacturing for hypoxic Hif1α-deletion T cells.
Shi and colleagues then demonstrated, in residing mice, that acetate supplementation was an efficient technique to bypass ICB resistance in tumor-bearing mice with particular deletion of HIF1α in T cells. When Hif1α-deletion tumor-bearing mice got acetate supplementation adopted by mixture ICB remedy, the mice had important enchancment in ICB remedy, as seen by potent suppression of tumor development and tremendously decreased tumor weights.
“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,” Shi stated. “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.”
“Our study, together with an early report by others, compellingly shows that the impaired HIF1α function in T cells is a major T cell-intrinsic mechanism of therapeutic resistance to ICBs, like anti-CTLA-4 and anti-PD-1/L1,” Shi stated.
Extra info:
Hongxing Shen et al, HIF1α-regulated glycolysis promotes activation-induced cell loss of life and IFN-γ induction in hypoxic T cells, Nature Communications (2024). DOI: 10.1038/s41467-024-53593-8
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College of Alabama at Birmingham
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HIF1α recognized as essential for T cell activation in oxygen-poor tumors (2024, December 14)
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