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

项目摘要 研究项目3 大约75%的头颈部鳞状细胞癌（HNSCC）患者接受化疗。 放射治疗，强调这种治疗方式对HNSCC的重要性。不幸的是，30-40%的 HNSCC患者由于放射抗性而局部复发。由于从完整的 人类肿瘤，HNSCC如何响应和适应放射治疗的生物学决定因素， 与化学疗法和/或免疫疗法的组合还没有被很好地理解。因此，迫切需要 阐明患者对放射治疗反应的生物学基础，以便这些知识可以 用于改善HNSCC的根除并减轻对正常组织的毒性。该提案将利用 从已完成的和拟议的分子生物学研究中纵向收集生物标本和多模式数据， 调强放射治疗（IMRT）再照射同时和辅助的表征试验 顺铂或nivolumab（一种PD-1抑制剂）治疗局部复发性HNSCC患者。放射治疗 至少部分是通过破坏DNA和激活免疫系统来起作用的。DNA损伤反应（DDR） 通过控制HNSCC对放射治疗和免疫治疗的抵抗， 检查点抑制（ICI）。值得注意的是，DDR基因在HNSCC中经常改变。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，ICI反应改善 3）在细胞群中存在独特的肿瘤抗原特异性祖细胞CD 8 + T细胞亚群（PD-1+ TCF-1+）， HNSCC可以被刺激分化成能够通过增强的neo- 在某些实施方案中，由APC进行的抗原呈递进一步由DDR失调驱动。然而， DDR指导这些免疫动力学和对ICI辐射的反应尚不清楚。我们假设 关键的DDR驱动蛋白控制HNSCC对放射治疗的内在获得性抗性， 化疗和/或ICI。我们建议：1）阐明遗传和微环境因素，支配 在HNSCC中，对放射治疗联合化疗与放射治疗联合ICI的反应和抵抗，2） 阐明DDR指导免疫动力学治疗的分子机制 3）确定HNSCC中驱动获得性抗性的分子机制 放射治疗加ICI与顺铂治疗。这项工作的完成将阐明独特的遗传 和微环境因素控制HNSCC的内在获得性抗性的连续体， 放疗联合化疗与放疗联合ICI，提供了详细的机制， 了解关键的DDR驱动蛋白如何控制HNSCC对放射治疗的抵抗， 化疗和/或ICI，并提供新的见解，如何DDR指导免疫反应动力学 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.