Researchers have discovered that activating the pentose phosphate pathway makes antitumor CD8+ T cells more likely to stay in an immature, stem-like, “precursor” state. Combining this metabolic reprogramming of T cells with a standard anticancer immune checkpoint inhibitor treatment leads to improvements in tumor control in animal models and in tumor organoids grown from human tumor samples. The findings suggest a potential strategy for enhancing the potency of anticancer immunotherapies.
This work is published in Nature Immunology in the paper, “Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy.”
“Our hope is that we can use this new metabolic reprogramming strategy to significantly boost patients’ response rates to immune checkpoint inhibitor therapies,” said Vivek Mittal, PhD, research professor of cardiothoracic surgery at Weill Cornell Medicine.
Active T cells eventually express immune-suppressing checkpoint proteins such as PD-1. Within the past decade, immunotherapies that boost anticancer immune responses by blocking the activity of these checkpoint proteins have had success in patients with advanced cancers. However, despite their promise, checkpoint inhibitor therapies tend to work well for only a minority of patients. That has spurred cancer biologists to look for ways of boosting their performance.
Here, researchers began by examining gene activity in cancer-fighting T cells within tumors, including tumors subjected to PD-1-blocking drugs. They found a connection between higher T-cell metabolic gene activity and lower T-cell effectiveness at fighting tumors.
The researchers then systematically blocked the activity of individual metabolic genes and discovered that blocking the gene for the metabolic enzyme PKM2 boosted the population of a precursor type of T cell, which can serve as a long-term source of 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.
“Targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2),” the authors wrote, “results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1high progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo.”
The researchers showed that the enhanced presence of these precursor T cells improved 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 Mittal.
Blocking PKM2 exerts this effect on T cells mainly by boosting the pentose phosphate pathway. “We found that we could reproduce this reprogramming of T cells just by activating the pentose phosphate pathway,” said Geoffrey Markowitz, PhD, a postdoctoral research associate in the Mittal laboratory.
More specifically, they wrote, “Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8+ T cells toward a TCF1high population, generated a unique transcriptional landscape and adoptive transfer of agonist-treated CD8+ T cells enhanced tumor control in mice in combination with PD-1 blockade and promoted tumor killing in patient-derived tumor organoids.”
The researchers’ 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. The group is currently 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.
Markowitz noted that the strategy might work even better for cell-transfer anticancer therapies such as CAR-T cell therapies, which involve the modification of the patient’s T cells in a laboratory setting followed by the cells’ 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.
