Dendritic cell redundancy enables priming of anti-tumor CD4 T cells in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is resistant to current immunotherapies and lacks effective CD8 T cell responses, which is potentially due to a paucity of cross-presenting dendritic cells (cDC1s). Here, we combine an innate immune adjuvant with anti-CTLA-4 and anti-PD-1 to achieve durable remissions and immunologic memory in multiple mouse models of poorly immunogenic PDAC. Tumor regression does not depend on CD8 T cells or tumor cell MHC class I expression but instead requires IFNγ-producing CD4 T cells (Th1s) that were primed by dendritic cells in lymph nodes. Combination immunotherapy induces an influx of activated cDC2s carrying tumor antigen into tumor-draining lymph nodes; cDC2s are required for orthotopic tumor clearance. Intratumoral CD4 T cells and cDC2s remain present in treatment-naïve and chemotherapy-exposed human PDAC. Even in chemotherapy-exposed patients’ blood, cDC2s outnumber cDC1s by ten-fold. Therefore, therapeutic targeting of the cDC2-CD4 T cell axis could be efficacious in pancreatic cancer.