Title: Towards Precision Immuno-Oncology: Unraveling the Genomic Determinants and Mechanisms Underlying Immunotherapy Efficacy and Resistance Immunotherapy has shown considerable promise for improving outcomes for cancer patients. Treatment of patients with antibodies against CTLA4, PD-1, or PD-L1 can result in dramatic responses and durable tumor control in some patients. However, most patients do not benefit and ICB treatment can cause severe side effects. Therefore, it is of paramount importance in the field to understand the mechanisms underlying sensitivity and resistance to ICB and other immunotherapies. The long-term goal of our research program is to unravel the molecular mechanisms underlying sensitivity and resistance to immunotherapies such as ICB and to work towards a better understanding of how to use immunotherapy in a precise and individualized manner. We propose to investigate how tumor and patient genetics/genomics affect tumor immune phenotypes and influence the response and resistance to immunotherapies. Over the next 7 years, our efforts will be focused on addressing three important questions with clear mechanistic and translational relevance. First, we will undertake a comprehensive analysis of how the diversity of mutational landscapes and densities, and DNA damage repair (DDR) deficiencies affect immunotherapy response in cancers treated with ICB (anti-PD1 or anti-CTLA4). This is aimed at developing and credentialing a precise model for ICB sensitivity and resistance to allow the design of rationale therapeutic combinations and personalization of ICB treatment. Second, we will use pre-clinical models and patient samples to evaluate how driver mutations in critical DDR mutations influence tumor immunity, ICB response, and acquired resistance. Third, we will characterize how the patient germline genotype (HLA), together with somatic mutation profiles of tumors, influence response to ICB.
This proposal focuses on elucidating the genetic determinants and mechanisms underlying immune checkpoint blockade therapy efficacy and resistance. We propose to use a combination of systematic large-scale genomics, preclinical animal modeling, integrated immunogenomics profiling, and mechanism-directed immunologic analyses to establish a robust understanding of sensitivity and resistance to immune checkpoint blockade. Our studies will build the foundation for the precise and individual application on immunotherapy for cancer patients.
