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

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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.