Humoral immunity in pancreatic cancer: B-cell heterogeneity, regulatory networks, and therapeutic opportunities.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a profoundly immunosuppressive tumor microenvironment and remains largely refractory to immunotherapy. Though T-cell-directed strategies have dominated the immunotherapy landscape, there is emerging data to suggest that B-cells and humoral immune products also have a critical role in PDAC pathobiology. However, therapies broadly targeting B-cells have failed in clinical trial, raising important questions regarding the complex, often contradictory roles for humoral immunity in PDAC development. Studies exploring humoral immunity in PDAC generally favor an immunosuppressive role. This occurs through several mechanisms including the accumulation of suppressive regulatory B-cells, paradoxical complement activation favoring immunosuppression and broad class switching skewed toward inhibitory immunoglobulin subclasses. However, in select contexts, secreted antibodies neutralize tumor antigens, facilitate antibody-dependent cytotoxicity, and coordinate anti-tumor responses within tertiary lymphoid structures. Here, we discuss the often-contradictory roles of humoral immunity in PDAC pathobiology, highlighting mechanisms contributing to T-cell exclusion, chemoresistance, and metastasis. We further discuss the role of humoral immunity in bolstering anti-tumor immune responses and need for biomarker guidance in future trials. These opposing roles in tumor development may explain the clinical failure of broad B-cell depletion strategies and offer opportunities for selective targeting of immunosuppressive populations while preserving anti-tumor humoral responses.