PROJECT SUMMARY – Tumor Microenvironment (TME) Program The Tumor Microenvironment (TME) Program at the USC Norris Comprehensive Cancer Center (NCCC) was created in 2003 and received a merit rating of Outstanding to Exceptional in 2015.The mission of this program is to discover basic mechanisms that control the interactions between cancer cells of viral and non-viral etiology and their microenvironment, leading to the identification of molecules or pathways that can be targeted for therapeutic interventions. The program has three scientific aims: 1) To investigate the fundamental mechanisms underlying cancer cell, immune cell and stroma cell interactions & communications; 2) To investigate the pathogenesis of cancer viruses and their immune escape mechanisms; and 3) To investigate the mechanisms underlying tumor immune escape and develop new approaches for cancer immunotherapy. The TME Program continues to be co-led by W. Martin Kast PhD who brings expertise in cancer virology & cancer immunology. The strategic recruitment of new co-leader Rongfu Wang PhD in 2019 expanded expertise in cancer immunotherapy, innate immune signaling, and immune cell epigenetics. Together, they promote intra- and inter-programmatic collaborations through Program meetings, retreats, seminars, and pilot funding mechanisms. The TME Program brings together 35 members from 10 departments in four schools at USC with expertise and research interest in tumor-stroma interactions, metastasis, inflammation, angiogenesis, cancer computational modeling, cancers induced by viruses (HPV, KHSV, HCV), and cancer immunology and immunotherapy. A unique aspect of this basic science Program is its commitment to clinical translation. In the current funding period, basic science discoveries by TME members led to four investigator- initiated clinical trials in the TACS and CCR programs. Research by the members has a unique impact on specific populations of the LA County catchment area, particularly children (neuroblastoma and childhood acute lymphoblastic leukemia (ALL)), Asians (liver cancer), and Hispanic women (breast cancer & HPV-induced cervical cancer). Also noteworthy is the collaboration with NCCC’s Cancer Research Training and Education Coordination (CRTEC) Program to provide TME-led cancer education of a very diverse group of students ranging from elementary school to junior faculty mentoring. During the current funding period, Program members have published 283 papers, of which 23% are intra-programmatic, 27% are inter-programmatic, 34% are multi- institutional and 29% are published in high impact journals including Nature Medicine, J. Clinical Investigation, Nature Communications, PNAS, JAMA Oncology, Cancer Discovery, Cell Metabolism, Hepatology, J Extracell Vesicles, ACS Nano, Cancer Res and Clinical Cancer Res. Program members hold $13.1M in cancer-related funding (direct costs); $11.2M is peer reviewed, of which $4.4M is from NCI, representing increases of 34% for overall and...