One of the most enduring mysteries in cancer immunology is why some CD8+ T cells respond to therapy and eliminate tumors while others do not and remain exhausted. This question has been at the forefront of the field because it is impossible to predict how cancer patients will respond to different treatment strategies. According to the current dogma, the CD8+ T cell compartment is comprised of a homogenous population of cells, and their fates depend on random environmental cues. However, we recently discovered that the CD8+ T cell pool is not uniform but instead comprised of developmental layers that are pre-programmed to respond in distinct ways. Our discovery raises the possibility that we might be able to predict how patients will respond to treatment based upon the starting composition of cells. Also, each developmental layer could be isolated for the development of more precise immunotherapies. However, all of our studies have been performed in the context of intracellular pathogens (bacteria, viruses). Thus, I am seeking funds to extend the developmental layering paradigm to tumor immunity, so that we can directly compare how different developmental layers of CD8+ T cells eliminate tumor cells and respond to checkpoint inhibitors. Since we are the only lab at Cornell that exclusively studies CD8+ T cells, we are in a prime position to generate novel tools for other researchers on campus and successfully compete for extramural funding in a new and exciting area of immunology.