Project 2: Role of radiation therapy in establishing cancer immunity

摘要 除了细胞对DNA的固有损伤外，辐射(RT)还可以对免疫系统产生全身性影响。AS 这样，最近的证据表明，免疫检查点阻断(ICB)对癌症的疗效可以 通过同时利用RT和ICB的组合策略进行了改进。然而，我们对 RT用于改善免疫介导的肿瘤反应的途径是有限的。此外，并不是所有的癌症 类型可能受益于ICB，无论是否有RT，可能需要额外的操作来增强 这些治疗方法对多种肿瘤类型的疗效。不断积累的数据指向模式的角色 通常负责感知病原体相关分子的识别受体(PRR) 激活先天免疫系统和优化免疫反应的模式。RT可能同样会促进 参与PRR通路，导致树突状细胞(DC)的激活，从而促进T细胞的交叉激发。 PRRs的类型，在肿瘤细胞中表达的PRRs的作用，与PRRs结合的配体的性质， 这些事件如何在RT后汇聚到DC功能还不是很清楚。因此，要 检测RT+α、CTLA4+αPD1联合治疗晚期肺癌的补体平行临床试验 癌症，这个项目试图调查RT如何通过PRRs介导免疫调节效应以及如何 这些信号事件被传递给DC，以增强T细胞库。为了扩大产品的种类 可能受益于RT+ICB的癌症，这项建议还研究了CD40的参与如何非 冗余激活树突状细胞以进一步提高应答，特别是对免疫原性低的肿瘤。因此，通过 了解RT的免疫调节作用机制、局限性及突破途径 治疗障碍，我们的目标是在下一代临床中将RT+ICB的疗效扩大到更多的患者 审判。

SUMMARY Besides cell intrinsic damage to DNA, radiation (RT) can have systemic effects on the immune system. As such, recent evidence indicates that the efficacy of immune checkpoint blockade (ICB) for cancer can be improved by combination strategies that utilized both RT and ICB. However, our understanding of the pathways that RT utilizes to improve immune-mediated tumor response is limited. Moreover, not all cancer types may benefit from ICB with or without RT, likely necessitating additional maneuvers to enhance the efficacy of these treatments for many tumor types. Accumulating data point toward a role for pattern recognition receptors (PRRs) that are normally responsible for sensing pathogen-associated molecular patterns to activate the innate immune system and optimize immune response. RT may similarly promote the engagement of PRR pathways, resulting in activation of dendritic cells (DCs) that facilitate T cell cross-priming. The types of PRRs, the role of PRRs expressed in tumor cells, the nature of the ligands that engage PRRs, and how such events might converge on DC function after RT are not well understood. Therefore, to complement parallel clinical trials that test the combination of RT + αCTLA4 + αPD1 in patients with advanced cancer, this project seeks to investigate how RT mediates immunomodulatory effects through PRRs and how these signaling events get relayed to DCs to enhance the T cell repertoire. In order to expand the types of cancers that may benefit from RT + ICB, this proposal also examines how engagement of CD40 can non- redundantly activating DCs to further improve response particularly for poorly immunogenic tumors. Thus, by understanding the immunomodulatory mechanism of action of RT, its limitations, and ways to break through therapeutic barriers, our goal is to broaden the efficacy of RT + ICB to more patients in next generation clinical trials.