P3: Molecular Mechanisms Underlying Therapy Response to Radiation and Immune Checkpoint BlockadeýSUBAWARD

项目总结 研究项目3 大约75%的头颈部鳞状细胞癌患者接受了 放射治疗，强调了这种治疗方式对HNSCC的重要性。不幸的是，30%-40%的 HNSCC患者由于放射抵抗而局部复发。由于源自完整的可用数据有限 人类肿瘤，HNSCC对放射治疗反应和适应的生物学决定因素及其 与化疗和/或免疫疗法的结合还不是很清楚。因此，迫切需要 阐明患者对基于辐射的治疗反应的生物学基础，以便这种知识能够 可用于促进HNSCC的根除和减轻对正常组织的毒性。这项提议将对 来自已完成和建议的分子的生物样本和多模式数据的纵向收集 调强放射治疗(IMRT)同期辅助性再照射的特征试验 局部复发的HNSCC患者使用顺铂或PD-1抑制剂nivolumab。放射疗法 至少在一定程度上，它通过破坏DNA和激活免疫系统发挥作用。DNA损伤反应(DDR) 通过调节HNSCC对放射治疗和免疫的抵抗力，在这一网络中发挥关键作用。 检查点抑制(ICI)。值得注意的是，DDR基因在HNSCC中经常发生改变。我们的初步数据 提示：1)DDR对辐射抗性的动态调节，2)DDR失调与 由于肿瘤突变负荷增加和肿瘤内免疫改变而改善的ICI反应 人群中，3)存在独特的肿瘤抗原特异性祖细胞CD8+T细胞亚群(PD-1+TCF-1+) HNSCC可能被刺激分化为能够通过增强的neo-1杀伤肿瘤的终末效应分子。 由DDR失调进一步驱动的APC的抗原提呈。然而，精确的机制是通过 目前还不清楚是哪种DDR引导了这些免疫动力学和对ICI的辐射反应。我们假设 关键的DDR驱动蛋白通过以下途径控制HNSCC对放射治疗的内在获得性耐药 化疗和/或脑梗塞。我们建议：1)阐明决定基因和微环境的因素 HNSCC化疗与ICI放射治疗的反应和耐药性2) 描述DDR指导基础治疗的免疫动力学的分子机制 ICI对辐射的反应，3)确定HNSCC获得性抗性的分子机制 放射治疗加ICI治疗与顺铂治疗比较。这项工作的完成将阐明独特的基因 以及控制HNSCC内在对获得性抗性连续体的微环境因素 化疗放射治疗与ICI放射治疗相比，提供了一个详细的机制 了解关键的DDR驱动蛋白如何控制HNSCC对放射治疗的耐药性 化疗和/或ICI，并为DDR如何指导免疫反应动力学提供了新的见解 作为对ICI放射治疗的反应。

PROJECT SUMMARY Research Project 3 Approximately 75% of head and neck squamous cell carcinoma (HNSCC) patients are treated with radiation therapy, highlighting the significance of this treatment modality for HNSCC. Unfortunately, 30-40% of HNSCC patients recur locoregionally due to radioresistance. Due to limited available data derived from intact human tumors, the biological determinants of how HNSCC respond and adapt to radiation therapy and its combination with chemotherapy and/or immunotherapy are not well understood. Thus, there is an urgent need to elucidate the biological basis of how patients respond to radiation-based therapies so that this knowledge can be exploited to improve eradication of HNSCC and mitigate toxicity to normal tissues. This proposal will leverage the longitudinal collection of biospecimens and multimodal data from both a completed and proposed Molecular Characterization Trial of intensity modulated radiation therapy (IMRT) re-irradiation with concurrent and adjuvant cisplatin or nivolumab, a PD-1 inhibitor, in patients with locoregionally recurrent HNSCC. Radiation therapy works, at least in part, by damaging DNA and activating the immune system. The DNA damage response (DDR) plays a critical role in this nexus by governing the resistance of HNSCC to radiation therapy and to immune checkpoint inhibition (ICI). Significantly, DDR genes are frequently altered in HNSCC. Our preliminary data suggest: 1) a dynamic regulation of radiation resistance by the DDR, 2) DDR dysregulation is associated with improved ICI response due to increased tumor mutational burden and alterations in intra-tumoral immune populations, 3) presence of a unique tumor antigen-specific progenitor CD8+ T-cell subset (PD-1+ TCF-1+) in HNSCC, which may be stimulated to differentiate into terminal effectors capable of tumor killing by enhanced neo- antigen presentation by APCs that is further driven by DDR dysregulation. However, the precise mechanisms by which DDR directs these immunologic dynamics and response to radiation with ICI are unclear. We hypothesize that key DDR driver proteins govern the intrinsic to acquired resistance of HNSCC to radiation therapy with chemotherapy and/or ICI. We propose to: 1) Elucidate the genetic and microenvironmental factors that govern response and resistance to radiation therapy with chemotherapy versus radiation therapy with ICI in HNSCC, 2) Delineate the molecular mechanisms by which the DDR directs immunological dynamics underlying therapy response to radiation with ICI, 3) Determine the molecular mechanisms driving acquired resistance in HNSCC treated with radiation therapy plus ICI versus cisplatin. Completion of this work will elucidate the unique genetic and microenvironmental factors governing the continuum of intrinsic to acquired resistance of HNSCC to radiation therapy with chemotherapy versus radiation therapy with ICI, provide a detailed mechanistic understanding of how key DDR driver proteins govern resistance of HNSCC to radiation therapy with chemotherapy and/or ICI, and provide new insights into how the DDR directs immunological response dynamics in response to radiation therapy with ICI.