Pancreatic cancer induces B cell lineage plasticity via Pax5 inhibition to sustain immunosuppression

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor characterized by its ability to create an immunosuppressive tumor microenvironment. Here, using robust 3D co-culture systems, samples from PDAC patients and murine in vivo models, we described a novel immune evasion mechanism used by PDAC to inhibit the anti-tumor activity of B lymphocytes: We provide evidence that pancreatic cancer suppresses the B cell-specific transcriptional program while enforcing their reprogramming into functional macrophages. Thus, we hypothesize that B cells undergo transdifferentiation under the influence of PDAC, by losing their lymphoid identity and acquiring a myeloid immunosuppressive phenotype. This drastic change is enacted by the loss of Pax5 expression. Importantly, our results showed that the Ex-B cells efficiently become phagocytic and produce soluble proteins that are known to enhance cancer cell survival and proliferation. This suggests that the PDAC-induced B cell to macrophage transdifferentiation pathway is functionally relevant and hence could serve as an immunotherapeutic target.