PROJECT SUMMARY The potential of checkpoint immunotherapy to combat cancer has been established in several cancer types. However, in pancreatic ductal adenocarcinoma (PDAC), checkpoint immunotherapy has not led to clinical benefit. Although multiple factors likely contribute, one significant factor is the extensive infiltration of PDAC by multiple lineages of immunosuppressive myeloid cells. Therefore, one promising therapeutic strategy is the targeting these myeloid cells to improve T cell-mediated immunity. These realizations have led to a significant number of clinical trials combining myeloid targeted agent with checkpoint immunotherapy. However, all current therapeutic strategies are subject to compensatory actions by untargeted subsets of monocytes, granulocytes, and/or tissue resident macrophages, which may ultimately limit therapeutic efficacy. To overcome this limitation, our team has developed a small molecule allosteric agonist of CD11b, ADH-503. Our data will clearly demonstrate: 1) CD11b-agonism both rapidly repolarizes TAMs to support anti-tumor immunity while simultaneously blunting the recruitment of multiple lineages of suppressive myeloid cells without the compensatory mechanisms seen with other myeloid-targeting agents. 2) CD11b-agonist-induce myeloid reprograming reawakens T cell immunity that in-turn significantly limit disease progression. 3) The combination of CD11b-agonist with checkpoint immunotherapy leads to dramatic tumor regression and long- term survival in PDAC models that are otherwise completely resistant to PD-1 therapy. These stunning data drive our hypothesis that CD11b agonism reprograms the TME to overcome resistance to checkpoint immunotherapy. To test this, we will: Aim 1: Determine the molecular mechanisms by which CD11b-agonism directly impacts myeloid cells. Aim 2: Determine the cellular mechanism(s) by which CD11b-agonism enhances T cell immunity. Aim 3: Determine if chemotherapy or radiation therapy better maximize the anti-tumor immunity and the efficacy generated by ADH-503 plus checkpoint immunotherapy. Impact: These studies investigate a new approach in current clinical development that can render PDACs responsive to immunotherapy.