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Enhancing T Cell Responses to Cancer Therapies Through Metabolic Reprogramming
A recent preclinical investigation led by researchers at Weill Cornell Medicine has identified a promising approach for improving the effectiveness of tumor-fighting T cells when used in conjunction with immune checkpoint inhibitor therapies. This study may pave the way for more potent anticancer immunotherapies.
Published on September 26 in Nature Immunology, the research highlights how the activation of a specific metabolic pathway known as the pentose phosphate pathway can help CD8 T cells, which play a crucial role in targeting tumors, to maintain a less mature, stem-like “precursor” state. By combining this metabolic reprogramming with standard immune checkpoint inhibitor treatments, the study observed significant enhancements in tumor control in both animal models and in human tumor-derived organoids.
Dr. Vivek Mittal, the senior author of the study and Ford-Isom Research Professor of Cardiothoracic Surgery at Weill Cornell Medicine, expressed optimism about the potential of this metabolic reprogramming technique to elevate response rates in patients undergoing immune checkpoint inhibitor treatments.
The lead author of the study, Dr. Geoffrey Markowitz, a postdoctoral research associate in Dr. Mittal’s lab, emphasized the significance of their findings.
Active T cells and other immune cells tend to eventually express immune-suppressive checkpoint proteins like PD-1. These mechanisms likely evolved to prevent uncontrolled immune responses. In the last decade, immunotherapeutic strategies that inhibit these checkpoint proteins have achieved notable success with advanced cancer patients. Nevertheless, these therapies are not universally effective, benefiting only a subset of patients, which has prompted further exploration into enhancing their efficacy.
Initially, the researchers analyzed gene expression in tumor-infiltrating T cells, particularly those exposed to PD-1 inhibitors. They found an intriguing correlation where increased metabolic gene activity in T cells was linked to diminished tumor-fighting capabilities.
The team then conducted experiments to inhibit specific metabolic genes and discovered that blocking the gene for the enzyme PKM2 produced a significant outcome: it increased the prevalence of precursor T cells, which can develop into mature cytotoxic CD8+ T cells capable of effectively combating tumors. Previous studies had indicated that PKM2 was associated with positive antitumor responses in anti-PD1 treatment contexts.
This bolstered population of precursor T cells was shown to correlate with improved results in animal models of lung cancer and melanoma being treated with anti-PD-1 therapies, as well as in human-derived organoid models of lung cancer.
“A larger pool of these precursors enhances our capacity for producing active cytotoxic CD8+ T cells that can more effectively target tumors,” stated Dr. Mittal, who is affiliated with Weill Cornell’s Sandra and Edward Meyer Cancer Center and Englander Institute for Precision Medicine.
The researchers determined that the enhancement of precursor T cells achieved by PKM2 inhibition primarily acts through reinforcing the pentose phosphate pathway—a critical metabolic route that contributes to the synthesis of essential molecules like DNA components.
“We demonstrated that activating the pentose phosphate pathway could replicate this T cell reprogramming,” Dr. Markowitz noted.
Ongoing studies aim to delve deeper into the mechanisms underlying this reprogramming. Early findings suggest that future therapeutic strategies could involve modifying T cells to augment their tumor-fighting capabilities in conjunction with checkpoint inhibitor therapies. Dr. Markowitz, along with Dr. Mittal and their team, is currently exploring collaborations with the Sanders Tri-Institutional Therapeutics Discovery Institute to develop agents that may induce such T-cell reprogramming for potential clinical applications.
Dr. Markowitz also suggested that this approach could be particularly advantageous for therapies like CAR-T cell treatments, in which T cells are genetically altered in a lab setting before being reintroduced into the patient. “By modifying the T cells directly in the laboratory, we can reduce the potential for off-target effects on other cell types,” he explained.
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