This application for continuation for the Specialized Program of Research Excellence (SPORE) in Head and Neck Cancer at the Johns Hopkins University School of Medicine supports a highly interactive, multidisciplinary, and intrainstitutional program. Five research projects, three cores, a career development and a research developmental program are proposed to carry out our translational research in head and neck cancer. The SPORE has given attention in all projects to the presence and absence of HPV infection as a major determinant of disease biology and behavior. Moreover, there are two main themes that permeate our major projects, one is genomics and biology and the other is immunology. Research Project #1- Augmentation of Immune Response to Head and Neck Squamous Cell Carcinoma via Phosphodiesterase Type 5 Inhibition - Co-Investigators, Ivan Borrello (basic) and Joseph Califano (clinic). Research Project #2 - HNSCC From Cancer Genomics to Personalized Biomarkers. - Co-Investigators, David Sidransky (basic) and Nishant Agrawal (clinic). Research Project #3 - Improving EGFR-targeted Immunotherapy of HNSCC by Counteracting TGF-ß-mediated Immune Suppression - Co-Investigators, Christine Chung (clinic) and AtuI Bedl (basic). Research Project #4 - HPV Vaccine Therapy - Co-Investigators Sara Pal (clinic) and T.C. Wu (basic) Project #5 - Etiologic Heterogeneity in Head and Neck Squamous - Co-Investigators, Gypsyamber D'Souza (basic) and Carole Fakhry (clinic) The cores support the research programs (Core #1 - Pathology/ Tissue Core, Dr. Westra; and Core #2 - Administrative/Clinical Core (Dr. Sidransky), Core #3 - Biostatistics and Bioinformatics Core (Dr. Rosner) The Career Development Program(Dr. Sidransky) aids the emergence of new investigators and the Research Developmental Program (Dr. David Sidransky) provides rapid funding of innovative directions.