New targets for overcoming immune checkpoint blockade resistance
Researchers have shown HIF1α as a key regulator that induces the cancer-killing capacity of T cells in hypoxic conditions.
A team of researchers from the University of Alabama at Birmingham (AL, USA) has demonstrated for the first time, the role of HIF1α in inducing interferon gamma (IFN-γ) in hypoxic environments, such as the tumor microenvironment. The team conducted a series of cell and mouse model studies to make this discovery. The role of HIF1α as a regulator of IFN-γ induction, which is known to induce the tumor-killing capacity of T cells, suggests it may be involved in the pathways that lead to the development of resistance to immune checkpoint blockade (ICB) therapies.
The initial clinical success of ICBs in various advanced cancers made them an emerging pillar of cancer care; however, therapeutic resistance to ICBs can create a plateau in their overall efficacy, particularly in solid tumors, resulting in a difficult clinical challenge for their progression. The hypoxic nature of the tumor microenvironment due to abnormal vasculature and altered metabolic activities adds a further burden to this challenge. Finding ways to overcome or disarm this resistance and reinstate anti-cancer tumor-infiltrating lymphocytes has become an important goal for many cancer clinicians.
While previous studies have clarified that HIF1α is not involved in IFN-γ induction and glycolysis under normal oxygen levels in the body, its role as a key regulator under hypoxic conditions remained unknown. To uncover the role of HIF1α, the team of researchers used a variety of techniques and pharmacological approaches: combining genetic mouse models, metabolic flux analysis using 13C-labeled glucose tracing assays and a Seahorse analyzer.
Let there be light: gene therapy targets cancer cells’ mitochondria
A light-induced gene therapy can damage cancer cells’ mitochondria, triggering widespread cancer cell death.
As a result of HIF1α deletion in both human and mouse T cells that were activated under hypoxia, the team was able to identify HIF1α as a key regulator of IFN-γ induction and activation-induced metabolic reprogramming in T cells. Further, the inhibition of glycolysis in T cells prevented IFN-γ induction, while knocking out a negative regulator of HIF1α increased IFN-γ induction in hypoxia.
When the team focused on cancer defense, they found that deletion of HIF1α in hypoxic T cells resulted in their reduced ability to kill tumor cells in vitro. In tumor-bearing mice, deletion of HIF1α in T cells resulted in ICB therapy resistance.
Further analysis revealed that loss of HIF1α in hypoxic T cells greatly reduced glycolytic activity, leading to depleted intracellular acetyl-CoA and reduced activation-induced cell death (AICD). When acetyl-CoA was restored by acetate supplementation in the growth medium, AICD was restarted and IFN-γ production restored in hypoxic HIF1α-null T cells.
The team then demonstrated that tumor-bearing mice with HIF1α deletion in T cells could overcome ICB resistance when supplemented with acetate, as seen by suppression of tumor growth and greatly reduced tumor weights.
These findings present exciting avenues for future research and highlight potential targets for overcoming ICB resistance. “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,” said Lewis Zhichang Shi, lead author of the study.
The study also highlighted that the FDA approval of acetate supplementation for other conditions may allow for a smooth transition of the study findings into translational and clinical investigations, and a rapid repurposing of acetate supplementation to effectively overcome ICB resistance.