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

癌症免疫学的一个中心挑战是解释自发性和自发性的个体间差异。 免疫疗法诱导免疫，然后在解释机制的基础上加强现有和 开发新的免疫疗法。基于对各种癌症的研究，总体上大幅增加 观察肿瘤中T细胞密度较高的患者的存活率。然而，目前仍不清楚的是 这就是为什么一些患者会产生强大的免疫反应，而另一些患者则具有无法检测到的免疫力。一系列 最近的研究报告说，具有高负载肿瘤突变的患者更有可能有持久的 对检查点阻断治疗的反应--用于MSI+CRC、吸烟者的肺癌和黑色素瘤。这个 目前的假设是，更多的突变产生更多的新抗原，为T细胞提供独特的靶点 识别肿瘤。因为建立强烈的免疫反应也需要特殊病原体的刺激 驱动先天免疫反应的传感器，我们假设强大的肿瘤免疫也可能 取决于病原体传感器的接合情况。我们最近发现，受损的DNA是从 在那里它触发刺痛的DNA传感通路，从而诱导细胞因子、趋化因子 以及随后的免疫反应，这是几个研究小组最近独立观察到的发现。我们建议 具有较高DNA损伤负荷的肿瘤可以通过刺痛和 增强保护性抗肿瘤免疫。进一步支持这一假设的是，我们已经鉴定了50个癌细胞 表达依赖叮咬的先天免疫反应的线条。因此，我们假设 DNA受损(或突变率)较高的肿瘤会触发肿瘤细胞内的DNA传感器，并且 诱导先天免疫反应，推动肿瘤的T或NK细胞排斥反应。这一假设具有很好的协同性。 假设更高的突变率会产生更多的新抗原，并解释了两者的诱导 先天免疫和获得性免疫是突变率和DNA损伤的函数。我们建议 综合测试受损DNA在驱动肿瘤免疫中的作用，使用细胞培养的组合 研究受损DNA在驱动先天免疫反应中的作用(目标1)；一种小鼠模型 确定肿瘤内受损DNA对肿瘤刺激性免疫排斥反应的影响 (目标2)；以及对人类结直肠癌和黑色素瘤的研究，以测试受损的 DNA、局部肿瘤免疫和临床结局(目标3)。因为我们的长期目标是发现 解释肿瘤免疫变化的机制，我们将采用公正的方法(目标3.2) 为肿瘤如何驱动或抑制人类肿瘤的免疫产生新的假说，结果已知。 我们的研究有望帮助解释肿瘤免疫的个体间差异，解决为什么 免疫治疗成功或失败控制肿瘤，并激发新的治疗靶点。

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.