Head & Neck Cancer Neoantigen Characterization & Therapeutic Targeting

项目摘要 头颈部鳞状细胞癌（HNSCC）目前显示出对以下药物的临床反应： 免疫检查点抑制剂，但其疗效仍然很低，在近20%的 治疗复发/转移患者。一种免疫学策略来改善这种低水平 有效率是针对HNSCC的高突变负荷，特别是那些与HNSCC相关的突变负荷。 长期接触烟草我们建议表征突变相关的新抗原 从在新辅助治疗中用纳武单抗治疗的患者获得的人HNSCC的概况 设置使用计算机和质谱法，以直接获得这些人的新， 表位结合这些研究，我们将描述免疫显性MHC 在体内自体人源化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，使用有效的STING扩增这些新抗原特异性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。结果 这一提议也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试验中与免疫检查点抑制剂联合给药 审判最后，我们的建议也将告知新表位预测算法和基于抗原的算法。 其他癌症类型的试验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.