PROJECT SUMMARY/ABSTRACT T cell immunotherapy have revolutionized cancer treatment, underscoring the ability of these cells in controlling tumor growth. Notwithstanding, T cell immunotherapy, heretofore, has only exploited effector T cells. Naïve T cells are the primordial substrate of T cell-mediated immunity. We and others have recently discovered that naïve T cells exist in distinct transcriptionally heterogenous states including clusters displaying a quiescent phenotype or expressing type I interferon response genes or IL-4 response genes or TCR pathway genes or memory-like genes. Naïve T cell heterogeneity is not fixed, but rather sensitive to genetic or environmental signals. Notably, changes in cluster composition induced by mutations or pathogen experience can have significant and, in some cases, diametrically opposite effects in the ability of naïve T cells to respond to cognate antigen. Here we put forward the innovative concept that naïve T cells are a repository of microbial experience. This in turn, establishes their future activation potential during cognate antigen encounter, including during anti-tumor immune response. We propose to: (1) test the effect of pathogen exposure on the transcriptional heterogeneity of naïve CD4+ and CD8+ T cells and (2) correlate these antigen-agnostic transcriptional changes intrinsic to naïve T cells for their effect on anti-tumor immune responses. Our approach will include testing a spectrum of microbial experiences (i.e.: bacterial, viral, and helminth infection) to comprehensively profile the effect of different types of infections. To establish the relationship between experience-moulded transcriptional states of naïve T cells and their ability to mount an anti-tumor immune response, we will test pathogen-conditioned naïve T cells in implanted and authoctonous tumor models. Our proposal has the potential to transform our understanding on how the environment shapes the immune state at the level of naïve T cells and the consequent impact on immunity, including anti-tumor immunity.