ABSTRACT Despite its aggressiveness and scarcity of mutated neo-epitopes, multiple lines of evidence support that ovarian carcinomas are truly immunogenic3-11. Understanding the nature of those responses and their dynamics specifically in ovarian cancer will be the focus of this competitive renewal. Key experimental findings supporting this proposal have been: 1) the identification of many ovarian cancers in TCGA datasets exhibiting strong markers of T cell-mediated cytolytic activity and ZERO missense mutations or frameshifts; 2) the fact that all of these immunogenic tumors without mutated neo-antigens show re-activation of endogenous retroviruses (ERVs); and 3) the identification of a new class of chimeric neo-antigens combining exons encoded by re-activated endogenous retroviruses plus exons from nearby protein-coding genes. Based on these and other of our findings, our central hypothesis is that immunogenicity in ovarian cancer is in part driven by the re-activation of endogenous retroviruses, resulting in the generation of chimeric antigens, so that ovarian malignancies become more - not less - immunogenic as the disease progresses in an immunosuppressive environment. In Aim 1, we will determine the role of retrovirally-driven chimeric antigens in immune protection against ovarian cancer. These results will validate the existence of a new class of tumor-specific antigens resulting from the re-activation of ERVs, which are expected to drive the immunogenicity of tumors with a limited repertoire of mutated neo-antigens. In Aim 2, we will define the role of re-activated endogenous retroviruses in the evolution of anti-tumor immunity. Supporting our preliminary results, these data are expected to substantiate a new framework to understand the dynamics and drivers of protective immunity against ovarian cancer, based on delayed but progressive immunogenicity, largely independent of mutated neo-antigens. In Aim 3, we will elucidate the mechanisms leading to the re-activation of ERVs in human ovarian cancer and, correspondingly, the intrinsic drivers of the immunogenicity. Our work will exert a profound effect in the field by substantiating a novel “suppressed cumulative immunogenicity” framework to explain the dynamics of anti-tumor immunity in tumors with a limited number of mutated of mutated neo-antigens but high expression of retroviral chimeric antigens, which will complement the understanding that the immunoediting hypothesis has provided for carcinogen-induced tumors.