A new preclinical study from Weill Cornell Medicine indicates that enhancing a vital metabolic pathway in T cells allows them to more effectively target tumors when used alongside immune checkpoint inhibitor therapy. This discovery points to a potential method to increase the effectiveness of cancer immunotherapies.
The research, published on September 26 in Nature Immunology, found that activating a metabolic pathway known as the pentose phosphate pathway helps antitumor CD8 T cells maintain a less developed, stem-like “precursor” state. The team demonstrated that applying this metabolic transformation to T cells in conjunction with standard immune checkpoint inhibitor treatments significantly improves tumor management in both animal models and human tumor organoids.
“We aim to leverage this novel metabolic reprogramming approach to substantially enhance patient responses to immune checkpoint inhibitor therapies,” explained Dr. Vivek Mittal, the senior author and the Ford-Isom Research Professor of Cardiothoracic Surgery at Weill Cornell Medicine.
The primary author of the study was Dr. Geoffrey Markowitz, a postdoctoral research associate in the Mittal lab.
When T cells and other immune cells become active, they eventually begin producing immune-suppressing checkpoint proteins, such as PD-1, which are thought to be important for regulating immune responses. Over the past ten years, immunotherapies that enhance anticancer immune responses by inhibiting these checkpoint proteins have achieved remarkable results in treating advanced cancers. However, despite their potential, these therapies only work effectively for a small percentage of patients, prompting researchers to explore ways to amplify their efficacy.
In this study, the team analyzed gene activity in T cells that fight cancer found within tumors, including those treated with PD-1 blockers. They uncovered a surprising relationship between increased metabolic gene activity in T cells and decreased functionality in tumor fighting.
By systematically inhibiting various metabolic genes, the researchers found that shutting down the gene responsible for the enzyme PKM2 had a notable and distinct impact: it increased the number of immature, precursor T cells, which can serve as a long-lasting source for more effective cytotoxic CD8+ T cells that attack tumors. Previous studies have linked this enzyme with enhanced antitumor responses during anti-PD1 treatment.
The researchers confirmed that the increased number of these precursor T cells resulted in improved outcomes in animal models of lung cancer and melanoma treated with anti-PD-1 therapy, as well as in a human-derived lung cancer organoid model.
“A greater pool of these precursors ensures a more consistent supply of active cytotoxic CD8+ T cells ready to combat tumors,” stated Dr. Mittal, who is also affiliated with the Sandra and Edward Meyer Cancer Center and the Englander Institute for Precision Medicine at Weill Cornell Medicine.
The team found that inhibiting PKM2 enhances this effect in T cells by increasing activity within the pentose phosphate pathway, which serves multiple roles including supplying building blocks for DNA and various biomolecules.
“We discovered that we could replicate this T-cell reprogramming just by activating the pentose phosphate pathway,” Dr. Markowitz noted.
Further investigations are underway to clarify the mechanisms behind this reprogramming. However, the outcomes already hint at the possibility of future treatments designed to modify T cells for greater efficiency in combating tumors in conjunction with checkpoint inhibitor therapy. Drs. Markowitz and Mittal, along with their team, are collaborating with the Sanders Tri-Institutional Therapeutics Discovery Institute on a project to develop agents aimed at inducing this T-cell reprogramming for upcoming clinical trials.
Dr. Markowitz mentioned that this strategy may have even greater efficacy when applied to cell-transfer cancer treatments like CAR-T cell therapies, which involve modifying a patient’s T cells in a lab before reintroducing them into the patient’s body.
“With the cell transfer technique, we can refine the T cells directly in the lab, thus reducing the likelihood of affecting other cell types inadvertently,” he explained.
