BTLA+CD200+ B cells dictate the divergent immune landscape and immunotherapeutic resistance in metastatic vs. primary pancreatic cancer

Response to cancer immunotherapy in primary versus metastatic disease has not been well-studied. We found primary pancreatic ductal adenocarcinoma (PDA) is responsive to diverse immunotherapies whereas liver metastases are resistant. We discovered divergent immune landscapes in each compartment. Compared to primary tumor, liver metastases in both mice and humans are infiltrated by highly anergic T cells and MHCII-lo IL10+ macrophages that are unable to present tumor-antigen. Moreover, a distinctive population of CD24 + CD44 – CD40 – B cells dominate liver metastases. These B cells are recruited to the metastatic milieu by Muc1 hi IL18 hi tumor cells, which are enriched >10-fold in liver metastases. Recruited B cells drive macrophage-mediated adaptive immune-tolerance via CD200 and BTLA. Depleting B cells or targeting CD200/BTLA enhanced macrophage and T-cell immunogenicity and enabled immunotherapeutic efficacy of liver metastases. Our data detail the mechanistic underpinnings for compartment-specific immunotherapy responsiveness and suggest that primary PDA models are poor surrogates for evaluating immunity in advanced disease. Overall design: For RNA-Seq experiments, mouse pancreatic primary tumors and liver metastatic tumors were harvested 3 weeks after orthotopic implantation and processed for bulk RNA-Seq. Alternatively, for single cell RNA-seq, CD45+ leukocytes were FACS-sorted from mouse pancreatic primary tumors or liver metastatic tumors 3 weeks after orthotopic implantation, and processed for 10X droplet-based single cell RNA-seq.