Tumor cell instrinsic DNA damage signaling to the immune response

摘要 DNA损伤癌症治疗的疗效取决于(I)固有的DNA修复 癌细胞的能力，以及(Ii)对来自肿瘤的信号的免疫反应。 了解DNA损伤和免疫之间通讯的分子基础 因此，反应是癌症病因学和治疗的中心问题。我们报道了 DNA损伤后有丝分裂进程允许cGAS依赖的模式识别 微核DNA启动干扰素刺激基因表达与T细胞依赖性 根除远处转移。DNA损伤诱导的细胞周期检查点中断 与p53突变一起导致DNA和DNA的模式识别受体反应 RNA传感器，包括cGAS-STING和MDA5和RIG-I/MAVS通路。我们的 未发表的发现揭示了这些反应的额外复杂性。NLRP9炎症体 染色体不稳定的癌细胞中的组装增加，并反对干扰素刺激 回应。有趣的是，在小鼠BRCA2突变体中，NLRP9缺乏延迟了肿瘤的形成 与免疫逆转相称的高级别浆液性卵巢癌模型 抑制性肿瘤微环境。这些发现可能解释了DNA损伤是如何 激活或抑制抗肿瘤免疫反应。 这项提议将采用细胞、生物化学和体内方法来检验假设 染色体不稳定性激活二分性炎症信号反应， 不同程度地影响肿瘤生长。这些机制对癌症的重要性 免疫疗法将在评估全身抗肿瘤的同基因肿瘤模型中进行测试 DNA损伤治疗与免疫检查点联合应用的免疫应答 封锁。与项目2和项目3以及与哺乳动物人工染色体的合作 化学生物学核心将对这些研究起到重要作用。

Summary The efficacy of DNA damaging cancer therapies is determined by the (i) intrinsic DNA repair capacity of cancer cells, and (ii) immune responses to signals emanating from tumors. Understanding the molecular basis of communication between the DNA damage and immune responses is therefore a central issue to both cancer etiology and therapy. We reported that mitotic progression after DNA damage allows cGAS-STING dependent pattern recognition of DNA in micronuclei to initiate interferon-stimulated gene expression and T-cell dependent eradication of distant metastases. Disruption of DNA damage induced cell cycle checkpoints together with p53 mutation resulted in pattern recognition receptor responses by both DNA and RNA sensors, including the cGAS-STING and the MDA5 and RIG-I/MAVs pathways. Our unpublished findings reveal additional complexity to these responses. NLRP9 inflammasome assembly is increased in chromosomally instable cancer cells and opposes interferon stimulated responses. Interestingly, NLRP9 deficiency delayed tumor formation in a murine Brca2 mutant high grade serous ovarian cancer model commensurate with reversal of an immune suppressive tumor microenvironment. These findings potentially explain how DNA damage can either activate or suppress anti-tumor immune responses. This proposal will take cellular, biochemical, and in vivo approaches to test hypotheses that chromosome instability activates dichotomous inflammatory signaling responses that differentially affect tumor growth. The importance of these mechanisms to cancer immunotherapy will be tested in syngeneic tumor models that assess systemic anti-tumor immune responses to combinations of DNA damaging therapies and immune checkpoint blockade. Collaborations with Projects 2 and 3, and with the Mammalian Artificial Chromosome and Chemical Biology Cores will be instrumental to these studies.