CANCER IMMUNOLOGY RESEARCH PROGRAM PROGRAM CODE: CI PROJECT SUMMARY/ABSTRACT The overarching mission of the Cancer Immunology (CI) Research Program is to improve understanding of the host response to cancer and to discover and test novel approaches to harness that response to improve patient outcomes. The program was ranked outstanding in the last renewal. Drs. Dhodapkar and Chen lead the CI program and are experienced investigators with a >15-year history of sustained NCI funding and multiple contributions in cancer immunology. Dr. Chen pioneered the targeting of the PD-1/PD-L1 pathway in cancer, which has transformed cancer immunotherapy. CI consists of 33 members from 8 different departments whose work revolves around four major aims: 1) understand the mechanisms underlying the capacity of the immune system to inhibit tumor growth, as well as mechanisms that drive tumor immune resistance;; 2) discover and test new approaches for promoting anti-tumor immunity;; 3) study the mechanistic links between inflammation and cancer;; and 4) undertake targeted therapeutic trials that utilize novel endpoint assessment and build on the fundamental discoveries of Aims 1-3. CI experienced a 15% increase in total funding ($12M direct), as well as a 21% increase in NCI funding ($2.3M direct). Collaborations remain strong with 17% intra- and 30% inter-programmatic publications. Translational efforts in the CI program are abundant, in particular with our tumor immuno-oncology (TIL) lab. Major collaborations exist with the Lung Cancer SPORE and SU2C efforts (DT), the GU/Bladder group (ST), the Phase I team (DT), Head and Neck Cancers (DT), and the colorectal cancer SU2C collaborative (CPC). Samples are being analyzed in numerous CI clinical trials to investigate the mechanisms underlying resistance and response to immune therapies. Human tissue has been collected under multiple protocols and used for patient-derived xenograft (PDX) and humanized models. During the last funding period, immune checkpoint blockade for cancer treatment has emerged as one of the most exciting and promising new approaches to treat cancer in decades. CI has played a leading role in bringing this revolutionary approach into the clinic with several seminal studies that introduced checkpoint blockade targeting the PD1/PD-L1 pathway in the therapy of melanoma, lung, gastric, head/neck, and bladder cancer. YCC has been at the forefront of the immuno-oncology revolution, playing lead roles in the earliest studies and, eventually, FDA approvals of immune checkpoint blockade and combination blockade, the identification of new checkpoint inhibitor targets, the development of unique animal models, and important advances in basic immunobiology, especially in T-cell biology. Over the last five years, the growth of our clinical trial efforts in this area has enabled reverse translation using clinical specimens, which bolsters SPORE and other multi-PI ...