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Impact of mutation burden on cancer growth and the immune landscape

突变负担对癌症生长和免疫环境的影响

基本信息

批准号：
10063504
负责人：
Shridar Ganesan
金额：
$ 64.44万
依托单位：
RBHS -CANCER INSTITUTE OF NEW JERSEY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063504
关键词：
Address Affect Animal Cancer Model Animal Model Antibodies Bypass CTLA4 gene Cancer Burden Cancer Model Cancer Patient Clinic Clinical Clinical Trials Combination immunotherapy Combined Modality Therapy DNA Polymerase III DNA-Directed DNA Polymerase Defect Development Generations Genetically Engineered Mouse Genome Goals Growth Hand Human Immune Immune response Immune system Immunocompetent Immunotherapy Induced Mutation KRASG12D Knowledge Lead Link Lung Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of thyroid Minority Mismatch Repair Mitochondria Modeling Mus Mutagenesis Mutation Nature Nuclear Oncogene Activation Oncogenes Oncogenic Patient-Focused Outcomes Patients Peptides Phenotype Physiological Play Polymerase Predisposition Resistance Role Signal Transduction Skin Solid Neoplasm Somatic Mutation Specimen T-Lymphocyte Testing Translating Tumor Immunity Wild Type Mouse anti-tumor immune response cancer therapy cancer type checkpoint therapy design immune activation immune checkpoint immune checkpoint blockade immunogenic melanoma mitochondrial genome mouse model neoantigens nonsynonymous mutation novel patient population programmed cell death protein 1 response success targeted treatment treatment strategy tumor tumor growth

项目摘要

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.

项目总结/文摘