Summary Patients with malignancy are nearly ten times more likely to develop sepsis than the general population, and cancer represents the most common co-morbidity in septic patients. Moreover, cancer is also the co-morbidity associated with the highest risk of death in sepsis, and hospital mortality can exceed 50% in patients with cancer and either sepsis or septic shock. However, the etiology behind the increased mortality seen in cancer patients who develop sepsis compared to healthy patients who develop sepsis is not well understood. This proposal aims to understand the cellular and molecular mechanisms by which the presence of cancer increases mortality during sepsis. We have identified and characterized distinct coinhibitory receptor profiles on CD4+ T cell populations in the setting of cancer and sepsis. Importantly, these differences are functionally relevant because some coinhibitory receptor blockade strategies have fundamentally different efficacy in the setting of cancer and sepsis compared to sepsis alone. First, we found that PD-1 blockade fails to improve survival during sepsis in animals with pre-existing malignancy even though this strategy is effective in sepsis alone. The mechanisms underlying this will be investigated in this proposal. Next, we found that TIGIT blockade is effective in preventing mortality from sepsis in animals with pre-existing malignancy, but interestingly is ineffective in sepsis in previously healthy animals. These results illuminate the fact that immunologic changes occurring as a result of pre-existing malignancy can impact the responsiveness to immunotherapy for sepsis, and highlight the need to design specific immunomodulatory therapies to reverse immune dysregulation in patients with cancer and sepsis. Finally, we have identified a pathway that may be responsible for the global changes in coinhibitory receptor expression and responsiveness in cancer septic hosts. IL-27 has been shown to potently regulate the expression of multiple coinhibitory receptors on the surface of T cells in models of both cancer and autoimmunity. Our preliminary data demonstrate a profound synergistic increase in serum concentrations of IL-27 in cancer septic hosts as compared to either sepsis alone or cancer alone, demonstrating that high serum IL-27 is associated with increased coinhibitory signaling in the setting of cancer and sepsis. Thus, the overarching hypothesis of this proposal is that increased levels of IL-27 present in cancer septic hosts results in the increased expression of T cell coinhibitory molecules on distinct subsets of CD4+ T cells, both regulatory and effector, that results in functional dysregulation of immune responses and increased mortality in cancer septic hosts. Interrogation of this hypothesis will elucidate novel immunotherapeutic pathways to control T cell coinhibitory receptor expression and improve mortality and immune dysregulation in cancer septic hosts.