A preclinical study conducted by researchers at Weill Cornell Medicine has found that stimulating a key metabolic pathway in T cells can enhance their effectiveness against tumors when combined with immune checkpoint inhibitor therapy. By activating the pentose phosphate pathway, the researchers found that antitumor CD8 T cells are more likely to remain in a precursor state, leading to improved tumor control in animal models and human tumor organoids grown in the laboratory. The goal of this research is to improve patients’ response rates to immune checkpoint inhibitor therapies.
The study’s lead author, Dr. Geoffrey Markowitz, and his colleagues discovered that blocking the gene for a specific metabolic enzyme called PKM2 had a significant impact on the population of less mature, precursor T cells in a way that boosts the production of more mature cytotoxic CD8+ T cells. This enzyme, which is involved in the pentose phosphate pathway, has been identified in previous studies as playing a role in producing effective antitumor responses in combination with anti-PD1 treatment. The researchers demonstrated that the presence of these precursor T cells resulted in better outcomes in animal models of lung cancer and melanoma, as well as in a human-derived organoid model of lung cancer.
By activating the pentose phosphate pathway, the researchers were able to reprogram T cells to be more effective at attacking tumors. The pathway plays a role in generating building blocks for DNA and other biomolecules, which are essential for the immune cells to function efficiently. The study’s senior author, Dr. Vivek Mittal, explained that having more precursor T cells allows for a sustained supply of active cytotoxic CD8+ T cells for attacking tumors. The researchers are currently investigating how this reprogramming occurs and are exploring the development of agents that can induce T-cell reprogramming for use in future clinical trials.
The researchers believe that this strategy could also be beneficial for cell-transfer anticancer therapies such as CAR-T cell therapies, where patient T cells are modified in a laboratory setting and then re-introduced into the patient. By manipulating the T cells directly in the lab, the risk of off-target effects on other cell populations can be minimized. The potential of this approach to improve the effectiveness of immune checkpoint inhibitor therapies and other anticancer treatments is promising, and further studies are underway to better understand the mechanisms behind this metabolic reprogramming of T cells.
Overall, the findings of this study suggest that targeting the pentose phosphate pathway to reprogram T cells could be a valuable strategy for enhancing the potency of anticancer immunotherapies. By boosting the population of precursor T cells and promoting the sustained production of active cytotoxic CD8+ T cells, this approach has the potential to improve the outcomes of immune checkpoint inhibitor therapies and other cancer treatments. Future research and clinical trials will further explore the therapeutic potential of this metabolic reprogramming strategy in the fight against cancer.