Background: Adenosquamous pancreatic cancer (ASQ) constitutes 1-5% of all pancreatic cancers and compared to pancreatic adenocarcinoma (PDAC) has a worse survival. ASQ has glandular and squamous histologic components and given its rarity and aggressiveness, in practice there is no current standard regimens for ASQ. Unfortunately, checkpoint blockade has had an overall disappointing impact on survival in PDAC. In an effort to identify a patient subgroup most likely to respond to immunotherapy, the immune tumor microenviroment (TME) in ASQ was evaluated. Tissue microarrays from archived ASQ samples were first created. Then immunocytochemistry (IHC) staining for immune cells and immune checkpoint proteins was performed. PD-L1 expression and the combined presence of PD-L1+, IDO+, LAG3+, and VISTA+ was seen. All ASQ cases had some degree of tumor infiltrating lymphocytes (TIL, including CD8+ T-cells). Furthermore, PD-L1 and other checkpoint positivity correlated with increased TIL. These findings suggest the presence of adaptive immune resistance. This is in contrast to standard PDAC, in which the expression of immune checkpoints is rarely accompanied by increased effector T-cells. Methods: We are conducting a multiple-center, single arm, phase II clinical trial to evaluate PD-1 inhibition with INCMGA00012 in locally advanced unresectable and metastatic ASQ patients. INCMGA00012 is a humanized monoclonal antibody antagonistic to PD-1. The primary objective is to determine the disease control rate at 4 months using RECIST 1.1. The study is planned with 21 evaluable subjects and allows early termination for lack of efficacy. Patients have a pre-treatment biopsy followed by INCMGA00012 500 mg on Day 1 of each cycle (every 4 weeks). A second biopsy will occur eight weeks later. Eligibility criteria includes histologically- or cytologically-proven adenosquamous carcinoma of the pancreas by central pathologic review and patients must have received (or been intolerant to or ineligible for) at least 1 prior line of cytotoxic chemotherapy and received no more than 2 prior systemic treatments. Patients with known MSI-H/dMMR status are excluded. Exploratory objectives include examining changes in the TME checkpoint expression and immune cell infiltrate in the biopsies via IHC and RNA expression studies. The clinical study was activated in February 2020. Clinical trial information: NCT04116073.