Targeting the immunologic vulnerabilities of small cell lung carcinoma

项目总结/摘要 该K 08提案描述了一个为期五年的肿瘤免疫学职业发展培训计划。纳文医生 R. Mahadevan在Brigham完成了解剖、分子和遗传病理学的临床培训， 妇女医院和哈佛医学院（HMS），并将继续这项研究计划的目标， 过渡到一个独立的实验室为基础的职业生涯调查细胞的内在和外在机制， 肿瘤微环境中的免疫调节，沿着诊断中临床服务的一小部分， 分子病理学 在这个培训项目中，Mahadevan博士将进一步发展肿瘤研究方面的专业知识。 免疫原性，并获得抗原发现和高分辨率幻灯片为基础的领域的新技能 表达谱分析，这将为他未来的研究提供重要信息。他的导师，博士大卫芭比（协理 Dana-Farber癌症研究所和HMS的医学教授），是翻译领域的领导者。 肿瘤免疫学，在指导学员方面有着出色的记录，包括那些成功地 成为主要学术中心的独立实验室教师。Mahadevan博士还召集了 一个在肿瘤免疫学方面具有互补专长的咨询委员会（Sharpe和Rodig博士）， 表观遗传学和免疫疗法（Uppaluri博士），计算基因组学（货车艾伦博士），以及广泛的 在指导医生-科学家走向独立职业方面的经验。Mahadevan博士将进一步补充他的 通过教学课程进行培训，以加深他的科学知识，领导能力和沟通能力，并将 定期在国内和国际会议上介绍其工作。 Mahadevan博士提出的研究的主要目标是阐明免疫学 小细胞肺癌（SCLC）的易感性。Mahadevan博士提供了初步数据， 抑制MHC I类（MHC I）抗原呈递的SCLC免疫原性亚型， 对患者的免疫检查点阻断有反应。该提案将利用对以下问题的新理解： SCLC免疫生物学，以合理地阐明这些不同的SCLC亚型的免疫脆弱性。 免疫学和功能检测将用于测试三个独立但相关的问题 从这一假设可以得出：（1）SCLC对MHC I去抑制的肿瘤微环境后果; (2)MHC I类分子降低小细胞肺癌对自然杀伤细胞介导的细胞毒作用的敏感性;（3）表观遗传学调控， MHC I限制性抗原在高MHC I SCLC中去抑制的潜在免疫原性。这些研究将导致 为了更深入地了解不同的SCLC免疫表型和伴随的抗肿瘤免疫应答， 这可能导致新的生物标志物的鉴定和有效的免疫疗法的发展。 难治性疾病

PROJECT SUMMARY/ABSTRACT This K08 proposal describes a five-year career development training program in tumor immunobiology. Dr. Navin R. Mahadevan has completed clinical training in Anatomic and Molecular and Genetic Pathology at Brigham and Women’s Hospital and Harvard Medical School (HMS), and will pursue this research program with the goal of transitioning to an independent laboratory-based career investigating cell-intrinsic and -extrinsic mechanisms of immune regulation in the tumor microenvironment, along with a minor component of clinical service in diagnostic molecular pathology. In this training program, Dr. Mahadevan will develop further expertise in the study of tumor immunogenicity, and acquire new skills in the areas of antigen discovery and high-resolution slide-based expression profiling, which will critically inform his future studies. His mentor, Dr. David Barbie (Associate Professor of Medicine at the Dana-Farber Cancer Institute and HMS), is an leader in the field of translational tumor immunology with an excellent track record in mentoring trainees, including those who have successfully become independent laboratory-based faculty at major academic centers. Dr. Mahadevan has also assembled an Advisory Committee with complementary expertise in tumor immunology (Drs. Sharpe and Rodig), epigenetics and immunotherapy (Dr. Uppaluri), and computational genomics (Dr. Van Allen), and extensive experience in mentoring physician-scientists to independent careers. Dr. Mahadevan will further supplement his training with didactic courses to deepen his scientific knowledge, leadership, and communication, and will regularly present his work at national and international meetings. The primary objective of Dr. Mahadevan’s proposed research is to elucidate the immunologic vulnerabilities of small cell lung carcinoma (SCLC). Dr. Mahadevan provides preliminary data identifying an immunogenic subtype of SCLC that depresses MHC Class I (MHC I) antigen presentation and may be responsive to immune checkpoint blockade in patients. This proposal will leverage this new understanding of SCLC immunobiology to rationally elucidate immunologically vulnerabilities of these distinct SCLC subtypes. Immunologic and functional assays will be employed to test three independent but related questions following from this hypothesis: (1) the tumor microenvironmental consequences of MHC I derepression by SCLC; (2) the sensitivity of MHC I low SCLC to natural killer cell-mediated cytotoxicity; (3) the epigenetic regulation and potential immunogenicity of MHC I-restricted antigens derepressed in MHC I high SCLC. These studies will lead to a deeper understanding of distinct SCLC immunophenotypes and attendant anti-tumor immune responses, which could lead to the identification of novel biomarkers and development of effective immunotherapies for this treatment-refractory disease.