(PQ3) The role of damaged DNA in inter-individual variation of tumor immunity

(PQ3) 受损DNA在肿瘤免疫个体间变异中的作用

• 批准号: 9750638
• 负责人: Nir Hacohen
• 金额: $ 50.26万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-26 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750638
• 关键词: Address; Affect; Animals; Autoimmunity; Automobile Driving; Cancer Control; Cancer Immunology Science; Cancer cell line; Cell Culture Techniques; Cell Line; Cell Nucleus; Cells; Clinical; Colorectal; Colorectal Cancer; Cytosol; DNA; DNA Damage; DNA Repair; Genetic; Goals; Human; Immune; Immune response; Immune system; Immunity; Immunologic Monitoring; Immunotherapy; Individual; Individual Differences; Innate Immune Response; Malignant Neoplasms; Malignant neoplasm of lung; Metastatic Melanoma; Mus; Mutation; Natural Immunity; Natural Killer Cells; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Process; Property; Reporting; Role; Sampling; Series; Smoker; Source; T-Lymphocyte; Testing; Tumor Burden; Tumor Cell Line; Tumor Immunity; Tumor-infiltrating immune cells; Variant; adaptive immunity; anti-tumor immune response; base; chemokine; colon cancer patients; cytokine; density; immune checkpoint blockade; inter-individual variation; melanoma; mouse model; neoantigens; neoplastic cell; new therapeutic target; novel; pathogen; programs; response; sensor; single-cell RNA sequencing; tumor; tumor growth

A central challenge in cancer immunology is to explain inter-individual differences in spontaneous and immunotherapy-induced immunity, and then build on the explanatory mechanisms to enhance existing and develop novel immunotherapies. Based on studies across diverse cancers, a substantial increase in overall survival is observed for patients with higher densities of T cells in their tumors. However, what remains obscure is why some patients develop powerful immune responses while others have undetectable immunity. A series of recent studies reported that patients with high loads of tumor mutations are more likely to have durable responses to checkpoint blockade therapy – for MSI+ CRC, lung cancer in smokers, and melanoma. The current hypothesis is that more mutations generate more neoantigens that provide unique targets for T cells to recognize tumors. Since mounting a strong immune response also requires stimulation of specialized pathogen sensors that drive innate immune response, we have hypothesized that potent tumor immunity may also depend on engagement of pathogen sensors. We recently discovered that damaged DNA is exported from nucleus to cytosol where it triggers the STING DNA-sensing pathway and thus induces cytokines, chemokines and subsequent immune responses, a finding observed recently by several groups independently. We propose that tumors with higher loads of damaged DNA could trigger intrinsic innate immune responses via STING and enhance protective anti-tumor immunity. Further supporting this hypothesis, we have identified 50 cancer cell lines that express a STING-dependent innate immune response constitutively. We thus hypothesize that tumors with higher loads of damaged DNA (or mutation rates) trigger DNA sensors within tumor cells, and induce innate immune responses that drive T or NK cell rejection of the tumor. This hypothesis synergizes well with the hypothesis that higher mutation rates produce more neoantigens, and explains the induction of both innate and adaptive immunity as a function of mutation rates and DNA damage. We propose to comprehensively test the role of damaged DNA in driving tumor immunity, using a combination of cell culture studies to study the role of damaged DNA in driving innate immune response (Aim 1); a mouse model to determine the impact of damaged DNA within a tumor on STING-dependent immune rejection of the tumor (Aim 2); and studies of human colorectal cancers and melanomas to test for associations between damaged DNA, local tumor immunity and clinical outcome (Aim 3). Since our long-term goal is to discover the mechanisms that explain variations in tumor immunity, we will employ an unbiased approach (Aim 3.2) to generate new hypotheses for how tumors drive or suppress immunity in human tumors with known outcome. Our studies are expected to help explain inter-individual variation in tumor immunity, address why immunotherapy succeeds or fails to control tumors, and inspire novel therapeutic targets.

癌症免疫学的一个核心挑战是解释自发性和恶性肿瘤的个体间差异