The advent of immune checkpoint inhibitors has transformed the treatment landscape for several advanced cancers, yet a plateau in therapeutic response has emerged due to resistance, impairing tumor-infiltrating lymphocytes (TILs). To counteract this resistance and revitalize anti-cancer TILs, which are central to targeting and eradicating tumor cells, remains a pivotal objective for oncologists. Notably, any intervention must contend with the atypical, hypoxic environment surrounding the tumor, characterized by rapid neoplastic growth and inefficient oxygen supply due to malformed vascular structures.
In groundbreaking research showcased in Nature Communications, Dr. Lewis Zhichang Shi and his team from the University of Alabama at Birmingham (UAB) delineate for the first time the indispensable role of HIF1a in T cells for inducing interferon gamma (IFN-γ) within hypoxic settings. IFN-γ plays a crucial role in enabling T cells’ tumoridisrupting capabilities. Equally, glycolysis—an alternative pathway for generating energy without oxygen—is requisite for IFN-γ production in T cells.
“Intriguingly, under normal oxygen-rich conditions, termed normoxia, the pathways leading to IFN-g production and glycolysis in T cells are not primarily controlled by HIF1a, even though it’s a central glycolysis regulator. Instead, it’s managed by its downstream mediator, LDHa,” Dr. Shi remarked. “Until now, the extent and manner of HIF1a’s involvement under hypoxic stress in modulating IFN-γ synthesis and glycolysis in T cells has been unclear.”
The UAB investigation confirmed that HIF1a-driven glycolysis is critical for driving IFN-γ in oxygen-starved T cells. As a subunit of the hypoxia-inducible factor (HIF), HIF1a orchestrates the cellular response to low oxygen.
Utilizing genetic mouse models, 13C glucose tracing via metabolic flux analysis, and pharmacological tactics, Shi and his team illuminated the essential nature of HIF1a. In both human and murine T cells activated in hypoxic scenarios, elimination of HIF1a obstructed the metabolic transition from catabolism to anabolism—anchored by anaerobic glycolysis—and hampered IFN-γ generation. Moreover, pharmacologically blocking T cells’ glycolysis under hypoxia curtailed IFN-γ induction. Conversely, enhancing HIF1a activity spurred IFN-γ even in low-oxygen conditions by negating a usual HIF1a suppressor.
In anti-cancer contexts, T cells deprived of HIF1a exhibited diminished tumor-eradicating ability in vitro. Tumor-laden mice with HIF1a-deficient T cells displayed no improvement with ICB therapy.
The study proposed a solution to bypass ICB resistance through acetate supplementation, sparking intracellular acetyl-CoA replenishment—which in turn, reengaged activation-induced cell death (AICD) and restored IFN-γ output in hypoxia-challenged, HIF1a-deficient T cells. This novel approach yielded encouraging results in ICB efficacy when applied to tumor-bearing mice models through acetate supplementation.
“Within the harsh metabolic tug-of-war of the tumor microenvironment, swaying the balance to favor TILs is paramount,” Shi advised. “Our findings illustrate that acetate can restore IFN-γ production in T cells lacking HIF1a and support recovery from ICB resistance.”
This body of work underpins the hypothesis that impaired HIF1a in T cells is a core barrier to ICB therapies like anti-CTLA-4 and anti-PD-1/L1, thus paving avenues for future therapeutic strategies.
Study collaborators include Hongxing Shen, Oluwagbemiga A. Ojo, and others from UAB, supported by contributions from the UAB Radiation Oncology and Pharmacology and Toxicology departments. Financial backing came in part from NIH grants and several foundations committed to advancing cancer research.