(Press-News.org) BIRMINGHAM, Ala. – 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. 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.
In a study published in Nature Communications, Lewis Zhichang Shi, M.D., Ph.D., and University of Alabama at Birmingham colleagues show, for the first time, how HIF1α in T cells is key for induction of interferon gamma, or IFN-γ, in that hypoxic environment. The cytokine IFN-γ is known to be essential to induce the tumor-killing capacity of T cells. Additionally, an alternative metabolism called glycolysis, which is able to produce energy in human cells when no oxygen is present, is similarly known 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,” said Shi, a professor in the UAB Department 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 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.
Shi and colleagues showed this key role for HIF1α in hypoxia by combining genetic mouse models, metabolic flux analysis using 13C-labeled glucose tracing assays and a Seahorse analyzer, as well as pharmacological approaches.
In both human and mouse T cells that were activated under hypoxia, they found 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 major component; the deletion also suppressed the induction of IFN-γ. Additionally, pharmacologic inhibition of T cell glycolysis under hypoxia prevented induction of IFN-γ. Conversely, stabilization of HIF1α by knocking out a negative regulator of HIF1α increased IFN-γ under hypoxic conditions.
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.
The researchers then showed a way to overcome that resistance to ICB therapy. Elucidation of the mechanistic function of the HIF1α deletion showed that loss of HIF1α greatly diminished glycolytic activity in hypoxic T cells, resulting in depleted intracellular acetyl-CoA and attenuated activation-induced cell death, or AICD. Restoration of intracellular acetyl-CoA by supplementing growth media with acetate reengaged AICD and rescued IFN-γ production for hypoxic Hif1α-deletion T cells.
Shi and colleagues then demonstrated, in living mice, that acetate supplementation was an effective strategy to bypass ICB resistance in tumor-bearing mice with specific deletion of HIF1α in T cells. When Hif1α-deletion tumor-bearing mice were given acetate supplementation followed by combination ICB therapy, the mice had significant improvement in ICB therapy, as seen by potent suppression of tumor growth and greatly reduced 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 said. “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 said.
Co-authors with Shi in the study, “HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells,” are Hongxing Shen, Oluwagbemiga A. Ojo, Haitao Ding, Chuan Xing, Abdelrahman Yassin, Vivian Y. Shi, Zach Lewis, Ewa Podgorska and James A. Bonner, UAB Department of Radiation Oncology; Logan J. Mullen, University of Alaska Fairbanks, Fairbanks, Alaska; M. Iqbal Hossain and Shaida A. Andrabi, UAB Department of Pharmacology and Toxicology; and Maciek R. Antoniewicz, University of Michigan, Ann Arbor, Michigan.
Support came from UAB; the O’Neal Comprehensive Cancer Center at UAB; National Institutes of Health grants CA230475-01A1, CA25972101A1 and CA279849-01A1; V Foundation Scholar Award V2018-023; Department of Defense-Congressionally Directed Medical Research Programs grant ME210108; and Cancer Research Institute CLIP Grant CRI4342.
At UAB Radiation Oncology and Pharmacology and Toxicology are departments in the Marnix E. Heersink School of Medicine. Shi is a scientist in the O’Neal Comprehensive Cancer Center and holds the Koikos-Petelos-Jones-Bragg ROAR Endowed Professorship for Cancer Research.
END
Key regulator that induces cancer-killing capacity in T cells under hypoxia is identified
The regulator HIF1α functions in a cancer-microenvironment that lacks oxygen, and it may be involved in resistance to immune checkpoint blockade therapy.
2024-12-13
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[Press-News.org] Key regulator that induces cancer-killing capacity in T cells under hypoxia is identifiedThe regulator HIF1α functions in a cancer-microenvironment that lacks oxygen, and it may be involved in resistance to immune checkpoint blockade therapy.