Saturday, November 23, 2024
11/23/2024
PROJECT SUMMARY/ABSTRACT Immune checkpoint blockade (ICB) using antibodies that disrupt PD1 or CTLA4 signaling can lead to durable responses in a wide variety of human cancers. Unfortunately, only a minority of patients obtain clinical benefit from ICB. A high non-synonymous nuclear mutation burden has been correlated with increased likelihood of response to ICB, suggesting that mutation induced neoantigens may underlie the tumor associated activation of immune checkpoints. Although this hypothesis linking mutation burden to peptide neoantigens is compelling, it has not been completely validated. Moreover, elevated mutation burden does not always dictate response to ICB, with some low mutation tumors such as thyroid cancers showing responses. Thus, there are huge gaps in our knowledge of the underlying mechanisms dictating response to ICB. We hypothesize that a high background somatic mutation burden, through introduction of mutations in DNA polymerases, will alter the immune landscape of cancers through the presence of truncal, tumor specific “neoantigens” that confer response to ICB. We will test this hypothesis and decipher underlying mechanisms using novel mouse models, This will be approached through the following specific aims: Aim 1: Determine the nature of the immune response to cancers with endogenous high nuclear mutation burden arising spontaneously in mice harboring germline proofreading mutations in Pold1 and Pole and patient tumors harboring POLE and POLD1 mutations.;; Aim 2: Determine how a high nuclear mutation burden affects the growth of oncogene-driven autochthonous cancer models and sensitivity to immune checkpoint therapy;; Aim 3: Determine if proofreading mutations in Polg and elevation of mitochondrial genome mutation burden contributes to an anti-tumor immune response.. Aim 4: Determine how combining targeted therapy and immune checkpoint therapy are modulated by presence of high background mutation burden. To address these aims, we will utilize mouse models in which a high background mutation rate is induced through germline proofreading mutations in Pole and Pold1 (for nuclear mutations) and Polg (for mitochondrial mutations. We will compare how specific oncogenes (Braf in skin and lung, and Kras in lung) induce tumors in either wild type mice or in mice with germline proofreading polymerase mutations to determine how high background mutation rate alters tumor growth, local and systemic immune response, and response to targeted therapy and ICB. Our overall goal is to develop a better understanding of how mutation burden affects the immune response to solid tumors. Robust models of high mutation burden cancers can be used to guide rational development of combination treatment strategies that can be translated into the clinic.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
