Nonredundant Immune Checkpoints Direct Therapeutic Resistance to Chemoimmunotherapy in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is characterized by a myeloid-enriched microenvironment and has shown remarkable resistance to immune checkpoint blockade (e.g., anti-PD-1 and anti-CTLA-4). In this study, we sought to define the role of myeloid immunosuppression in immune resistance in PDA. We report that although depletion of CSF1R+ myeloid cells in combination with anti-PD-1 and chemotherapy triggers T-cell infiltration into PDA, it also causes compensatory remodeling of the myeloid compartment with limited tumor control. Combination therapy against multiple myeloid targets, including CSF1R, CCR2/5, and CXCR2, was insufficient to overcome treatment resistance. High-dimensional single-cell analyses performed on T-cell infiltrates in human and mouse PDA revealed upregulation of multiple immune checkpoint molecules, including PD-1, LAG-3, and CTLA-4. Combinatorial blockade of PD-1, LAG-3, and CTLA-4 along with chemotherapy and anti-CSF1R was necessary to trigger activation of peripheral CD4+ and CD8+ T cells and led to deep, durable, and complete tumor responses, with each immune checkpoint blockade agent contributing to efficacy. Our findings indicate that a comprehensive approach targeting both negative regulatory signals controlling T-cell function and the myeloid compartment will be fundamental to unveiling the potential of immunotherapy in PDA.