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.