Stimulating a key metabolic pathway in T cells can enhance their effectiveness against tumors when used with immune checkpoint inhibitor therapy, according to a preclinical study from Weill Cornell Medicine researchers. The findings suggest a potential strategy for boosting anticancer immunotherapies.
Activating Pentose Phosphate Pathway
The study, published in Nature Immunology, revealed that activating the pentose phosphate pathway makes antitumor CD8 T cells more likely to remain in an immature, stem-like, “precursor” state. Combining this metabolic reprogramming of T cells with a standard anticancer immune checkpoint inhibitor treatment led to significant improvements in tumor control in animal models and tumor organoids grown from human tumor samples.
"Our hope is that we can use this new metabolic reprogramming strategy to significantly boost patients’ response rates to immune checkpoint inhibitor therapies," said senior author Dr. Vivek Mittal, the Ford-Isom Research Professor of Cardiothoracic Surgery at Weill Cornell Medicine.
T Cells and Checkpoint Proteins
T cells and other immune cells, when active, start to express immune-suppressing checkpoint proteins such as PD-1, which are thought to keep immune responses from running out of control. Immunotherapies that block the activity of these checkpoint proteins have shown success in treating advanced cancers. However, checkpoint inhibitor therapies tend to work well for only a minority of patients, spurring cancer biologists to seek ways to improve their performance.
Blocking PKM2 Boosts T Cell Precursors
The researchers examined gene activity in cancer-fighting T cells within tumors, including tumors treated with PD-1-blocking drugs. They found a connection between higher T-cell metabolic gene activity and lower T-cell effectiveness. Blocking the gene for the metabolic enzyme PKM2 boosted the population of a less mature, precursor type of T cell, which can serve as a long-term source of more mature tumor-fighters called cytotoxic CD8+ T cells. This enzyme had also been identified in prior studies as more likely to produce effective antitumor responses in the context of anti-PD1 treatment.
The enhanced presence of these precursor T cells brought better results in animal models of anti-PD-1-treated lung cancer and melanoma, and in a human-derived organoid model of lung cancer.
"Having more of these precursors enables a more sustained supply of active cytotoxic CD8+ T cells for attacking tumors," said Dr. Mittal, who is also a member of the Sandra and Edward Meyer Cancer Center and the Englander Institute for Precision Medicine at Weill Cornell Medicine.
Metabolic Pathway
The researchers found that blocking PKM2 exerts this effect on T cells mainly by boosting the pentose phosphate pathway, whose functions include generating building blocks for DNA and other biomolecules. "We found that we could reproduce this reprogramming of T cells just by activating the pentose phosphate pathway," said Dr. Markowitz.
Further studies are underway to determine more precisely how this reprogramming occurs. The findings point to the possibility of future treatments that would alter T cells in this way to make them more effective tumor fighters in the context of checkpoint inhibitor therapy. Drs. Markowitz and Mittal and their colleagues are discussing with the Sanders Tri-Institutional Therapeutics Discovery Institute a project to develop agents that can induce T-cell-reprogramming for use in future clinical trials.
This strategy might work even better for cell-transfer anticancer therapies such as CAR-T cell therapies, which involve modifying the patient’s T cells in a laboratory setting followed by re-infusion into the patient. "With the cell transfer approach, we could manipulate the T cells directly in the lab dish, thereby minimizing the risk of off-target effects on other cell populations," he said.
