HAT Inhibition to Impair Foxp3+ Treg Function and Boost Anti-Tumor Immunity

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DESCRIPTION (provided by applicant): Cancers are a leading cause of death and in efforts to reduce the incidence of the cancer, and especially recurrence after chemotherapy and/or radiation; investigators have repeatedly sought to increase the immunogenicity of cancers so as to promote host anti-cancer immune responses. These efforts have largely been unsuccessful, but much evidence now points to a role of host Foxp3+ T regulatory (Treg) cells in limiting anti-tumor immunity. Hence, the ability to decrease Treg function may be of major therapeutic significance if this can be done incrementally and without full-scale depletion of Tregs that are essential to maintenance of immune homeostasis and prevention of autoimmunity. Histone/protein acetyltransferases (HATs) promote chromatin remodeling by acetylating histone tails but also regulate the activities of >1750 proteins. The effects of genetic or pharmacologic targeting of the various classes of HATs on immune responses are largely unknown. Based upon preliminary data we hypothesize that one or more HATs will be key to regulation of Foxp3+ Treg functions. Accordingly we will investigate: Aim 1) What HATs are expressed by Tregs and how does their targeting by genetic and/or pharmacologic approaches affect Treg function in vitro? Since preliminary data points to roles for the HATs, PCAF and p300, in control of Treg suppression, we will analyze the relative contribution of these HATs to regulation of Treg vs. non-Treg biology, including acetylation of Foxp3 itself. Aim 2) To determine whether the in vitro insights obtained from studies of Aim 1 can translate to actual therapies, we will models of Treg-dependent transplant tolerance to test whether targeting of p300 or other HATs so implicated can regulate Treg functions in vivo without concomitant suppression of T cell responses. Aim 3) To determine whether strategies to impair Treg function without their depletion can boost host anti-cancer immune responses, we will test the effects of HAT targeting through genetic and pharmacologic approaches in murine models of lung cancer. These studies in immunocompetent hosts will assess whether HAT targeting can dampen Treg functions and allow host immune responses to curtail the growth and spread of primary and recurrent tumors. The studies proposed will dissect the functions of HATs in Tregs and test whether these molecules provide key therapeutic targets for manipulation of the immune responses, especially in those circumstances when reduction of Treg suppression is desirable. Hence, our studies should have major consequences for development of new strategies for immunotherapy in patients with malignancies, and likewise may have consequences for management of patients with HIV or other chronic infections. PUBLIC HEALTH RELEVANCE: We will investigate how cancers can grow and spread in individuals despite an intact immune system, focusing on the role of host Foxp3+ T regulatory (Treg) cells in limiting anti-tumor immunity. We will identify the histone/protein acetyltransferase enzymes (HATs) required for Treg function, and test whether HAT inhibition will decrease Treg functions and thereby allow host immune responses to control the growth and spread of tumors. Our studies may identify new therapies for patients with malignancies, and may also have consequences for management of patients with HIV or other chronic infections.