Pharmacologic Inhibition of the Glycolytic Pathway Improves Response to Immune Checkpoint Blockade
Harnessing the immune system to battle cancer using immune checkpoint blockade (ICB) has revolutionized cancer treatment for many patients. However, a significant proportion of patients are resistant to these therapies, often due to a hostile tumor microenvironment. This microenvironment is unfriendly to anti-tumor immune cells, such as effector T cells, rendering immunotherapies less effective. One factor contributing to an immunosuppressive tumor microenvironment is the overconsumption of glucose and overproduction of lactic acid by tumor cells. This overreliance on glucose metabolism by tumor cells spares less glucose for effector T cells to consume, and the excess lactate is detrimental to effector T cell function. Therefore, we proposed 24 combining immunotherapy with an inhibitor of key enzyme lactate dehydrogenase (LDH), which catalyzes the final step of glucose metabolism, to alleviate glycolysis-mediated immunosuppression in the tumor microenvironment. Cancer patients with an elevated serum LDH level tend to have a lower probability of survival, and we observed that serum lactate and LDH levels correlate with primary tumor burden in mice. We recently demonstrated that genetic dampening of LDH in a mouse-model of breast cancer results in improved and long-lasting anti-tumor responses to CTLA-4 blockade in mice. We found that administration of a small molecule inhibitor of LDH reduces tumor lactate production and glucose consumption without inhibiting anti-tumor T-cell killing. When administered to mice, the LDH inhibitor has a slight anti-tumor effect on its own, and when combined with immune checkpoint (CTLA-4) blockade, LDH inhibition is more effective in slowing melanoma growth than immunotherapy alone. We have shown that this combination therapy enhances effector T cell function, while destabilizing the function of protumorigenic immune cells in the tumor microenvironment. This study provides foundational, mechanistic research that will inform the use of metabolic inhibitors alongside immunotherapies in clinical trials to combat resistance to immunotherapy and improve cancer patient outcomes.
The PhRMA Foundation has been instrumental in providing me with the resources required to push forward my research on cancer drug targets to combat resistance to immunotherapies. I’m privileged to represent a foundation focused on innovative science that directly translates to improving the lives of patients.