Head & Neck Cancer Neoantigen Characterization & Therapeutic Targeting

项目摘要 头颈部鳞状细胞癌(HNSCC)目前对 免疫检查点抑制剂，但其疗效仍然很低，近20% 治疗复发/转移患者。改善这一低水平的一种免疫策略 有效率是针对HNSCC的高突变负担，特别是与 长期接触烟草。我们建议对突变相关的新抗原进行表征。 从新佐剂中接受尼伏单抗治疗的人HNSCC的景观 设置同时使用电子计算机和质谱学方法直接获得这些人的neo- 表位。结合这些研究，我们将描述免疫优势的MHC 体内自体人源化小鼠系统中的限制性新抗原。这些发现将 帮助指导一种新的策略，利用有效的刺痛来扩增这些新抗原特异的T细胞 激动剂配制的纳米颗粒与人HNSCC中发现的已知新抗原。发现 这项提案还将影响基于新抗原的癌症疫苗应该如何 在未来的头颈部临床中与免疫检查点抑制剂联合使用 审判。最后，我们的建议还将用于新表位预测算法和基于抗原的 其他癌症类型的试验将对整个癌症免疫学领域产生深远影响。

Project Summary Head & neck squamous cell carcinoma (HNSCC) is currently showing clinical response to immune checkpoint inhibitors, but its efficacy is still low at nearly 20% of the recurrent/metastatic patients treated. One immunological strategy to improve upon this low efficacy rate is to target the high mutational burden of HNSCC, particularly those associated with chronic tobacco exposure. We propose to characterize the mutation associated neoantigen landscape of human HNSCC obtained from patients treated with nivolumab in a neoadjuvant setting using both in silico and mass spectroscopy methods to directly obtain these human neo- epitopes. In conjunction with these studies, we will characterize the immunodominant MHC restricted neoantigens in an autologous humanized murine system in vivo. These findings will help direct a novel strategy to expand these neoantigen-specific T-cells using a potent STING agonist formulated nanoparticles with known neoantigens found in human HNSCC. Findings from this proposal will also impact how neoantigen-based cancer vaccines should be administered in conjunction with immune checkpoint inhibitors in future head and neck clinical trials. Lastly, our proposal will also inform neoepitope prediction algorithms and antigen based trials for other cancer types to have deep impact in the field of cancer immunology as a whole.