Naive T cells in Cancer Immune Evasion and Immunotherapy

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T cells are the main effector components of anti-tumor immunity in the majority of cancer types. The phenotypic and functional heterogeneity of memory T cells in the human cancer environment have been the focus of recent studies. We and others have shown that the metabolic alteration in the cancer microenvironment can directly mediate memory and effector T cell dysfunction. However, it is unknown whether naïve T cells are targeted and altered by cancer metabolism in patients with cancer, particularly in patients with advanced cancer. PD-L1 and PD-1 blockade and other types of checkpoint therapy target, rescue, and promote effector T cell function to achieve clinical response. However, it is unknown if and how naïve T cells are involved in the current cancer immunotherapy-mediated mechanisms. There is a balanced loss and replacement of naïve T cells in the periphery. The molecular basis of naïve T cell quiescence has been studied in homeostasis in mice. However, the nature of naïve T cells is poorly defined in patients with cancer and in tumor bearing mouse models under homeostatic situation and immunotherapeutic settings. Alteration of naïve T cells may likely affect T cell homeostasis and memory T cell differentiation and functionality in the tumor bearing hosts. Thus, it is time to systemically study the nature of naïve T cells in tumor bearing hosts. In the current proposal, we will investigate the functional and molecular features and therapeutic relevance of naïve T cells in patients with ovarian cancer and in several tumor bearing mouse models. Our specific aims are: Aim 1 is to test our hypothesis that autophagy malformation is a molecular feature of naïve T cells in tumor. Aim 2 is to determine the molecular mechanisms of FIP200 loss in naïve T cells in tumor. Aim 3 is to test our hypothesis that FIP200 in naïve T cells affects spontaneous and therapy-induced tumor immunity.