TCF1high progenitor CD8+ T cells can mediate the efficacy of immunotherapy, but researchers are currently unclear about the molecular mechanisms behind their generation and maintenance. Recently, in a research report published in the international journal Nature Immunology, entitled "Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy", scientists from Weill Cornell Medical College and other institutions found through a preclinical study that stimulating key metabolic pathways in T cells may enable them to more effectively resist and fight tumors when combined with immune checkpoint inhibitor therapy. This research finding may help researchers develop new potential strategies to enhance the potential of anti-cancer immunotherapy.
Researchers have found that activating a metabolic pathway called the pentose phosphate pathway may make anti-tumor CD8+ T cells more likely to remain in an immature, stem-like precursor state. Combining metabolic reprogramming of T cells with standard anti-cancer immune checkpoint inhibitor therapy may greatly improve tumor control in animal models and tumor "organoids" grown from human tumor samples. "Our hope is that we can use this metabolic reprogramming strategy to significantly improve patients' response to immune checkpoint inhibitor therapy," said Professor Vivek Mittal.
When T cells and other immune cells are in an active state, they eventually begin to express immunosuppressive checkpoint proteins such as PD-1, which are thought to have evolved to prevent immune responses from getting out of control. Over the past decade, immunotherapies that enhance the body's anti-cancer immune response by blocking these checkpoint proteins have achieved some amazing results in patients with advanced cancer. However, despite its great potential, checkpoint inhibitor therapy tends to work only in a minority of patients, which may have prompted cancer biologists to begin looking for new ways to improve the performance of this therapy.
In this latest study, the researchers began to analyze the gene activity of anti-cancer T cells in tumors, including tumors treated with PD-1 blocking drugs. They found that there may be a very puzzling connection between higher T cell metabolic gene activity and lower T cell anti-tumor effectiveness. The researchers then systematically blocked the activity of individual metabolic genes and found that blocking the gene encoding a metabolic enzyme called PKM2 may have a significant and unique effect, that is, it increases the number of less mature precursor T cells, which can serve as a long-term source of cytotoxic CD8+ T cells, a more mature anti-tumor defender. In previous studies, researchers believed that the PKM2 enzyme may be more likely to produce a more effective anti-tumor response in the context of anti-PD-1 therapy. The researchers pointed out that the enhancement of these precursor T cells did produce better treatment effects in animal models of lung cancer and melanoma treated with anti-PD-1, as well as in human-derived lung cancer organoid models.
Figure 1. Pentose phosphate pathway agonism results in tumor control in murine and human model systems. (Markowitz G J, et al., 2024)
"Having more of these precursors may allow for a continuous supply of active cytotoxic CD8+ T cells to attack tumors," said Dr. Mittal. "We found that blocking PKM2 may exert its effects on T cells by primarily enhancing a metabolic pathway called the pentose phosphate pathway, which has multiple functions, including producing building blocks for DNA and other biomolecules."
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The researchers also found that simply activating the pentose phosphate pathway recapitulated the reprogramming of T cells. The researchers are now working to more precisely determine how this reprogramming process occurs. But their findings point to the possibility of developing future therapies and whether such therapies could alter T cells to make them more effective fighters against tumors in the context of checkpoint inhibitor therapy.
The researchers note that this strategy may work better for cell transfer anti-cancer therapies, such as CAR-T cell therapy, which involves modifying a patient's own T cells in the laboratory and then infusing them back into the patient. With this cell transfer approach, researchers can directly manipulate T cells in a laboratory dish, minimizing the risk of off-target effects on other cell populations.
Reference
Markowitz G J, et al. Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy. Nature Immunology, 2024: 1-16.