The role of the immune system is to survey the body in search of dangerous “non-self” elements and to eliminate them without damaging the host. Cancer is a disease which develops when host cells genetically change and begin growing in an uncontained fashion. It was therefore thought for many years that the immune system was incapable of recognizing or eliminating cancer cells due to their emergence from, and similarity to, “self” elements. The remarkable discovery that blocking signals (“immune checkpoints”) that restrain the ability of immune cells to recognize and destroy foreign elements can enable the immune system to treat cancer has fundamentally changed our approach to the treatment of these patients. Even in the setting of immune checkpoint inhibitors, however, immune cells lose functionality within tumors as part of a stepwise process known collectively as T-cell “exhaustion.” Reversing T-cell exhaustion is essential to make immunotherapy a viable treatment for all patients.
Our laboratory recently discovered that the metabolism of T-cells – the way that cells take up, break down, and utilize nutrients – becomes dysfunctional within tumors and, and moreover that this metabolic switch is required for T-cells to become fully exhausted. In work supported by the V foundation, we will understand how tumors exploit this metabolic dysfunction by creating metabolically inhospitable environments in which T-cells lose their capacity to control tumor growth. By identifying and reversing these environmental barriers, we hope to reverse or prevent T-cell exhaustion and make immunotherapy a viable strategy for every patient.