Abstract B62: The role of B regulatory cells in pancreatic cancer
Authors: Pylayeva-Gupta Yuliya , Handler Jesse S. , Hajdu Cristina , Bar-Sagi Dafna 
Published: October 2015

Background: Formation of pancreatic ductal adenocarcinoma (PDA) is accompanied by pronounced changes in stromal responses and immune surveillance programs, which are now recognized as some of the major drivers in PDA tumor evolution, and likely contribute to its notorious resistance to therapy. However, the cellular and molecular mechanisms that underlie immune response modulation in the context of pancreatic tumorigenesis remain poorly understood. We have observed that B lymphocytes accumulate at sites of pancreatic neoplasia and infiltrate lesion-adjacent stroma. The role of B-cell-mediated immune regulation in solid cancers has only recently begun to be appreciated, and virtually nothing is known about B cell function in pancreatic tumorigenesis. Our studies test the role of B cells in the initiation of pancreatic cancer and provide novel insight into functions of B regulatory cells in cancer pathogenesis.

Experimental Design and Methods: In this study, we orthotopically grafted KRasG12D- pancreatic ductal epithelial cells (PDEC) into pancreata of recipient mice with normal or selectively immunocompromised immune responses. In particular, we investigated the role of B lymphocytes in pancreatic neoplasia by implanting KRasG12D-PDEC into the B cell deficient μMT strain, and evaluated the role of specific B cell subsets using adoptive lymphocyte transfer.

Results: We demonstrate that B lymphocytes are specifically expanded in pancreatic neoplasia. We find that rather than being restricted to peri-pancreatic lymph node tissue, B cells infiltrate human PanIN lesions, as well as both LSL-KRasG12D; p48-Cre (KC) and pancreata orthotopically grafted with KRasG12D-PDEC. Such infiltration is closely correlated with expression of the B cell chemoattractant CXCL13 in the stromal compartment of the pancreas. Transplantation of KRasG12D-PDEC into pancreata of syngeneic B cell deficient μMT mice resulted in reduced growth of the cancer cells, indicating that B cells exert a tumor promoting effect. This defect in growth of KRasG12D-PDEC was accompanied by robust infiltration of macrophages. We found that pancreata-associated macrophages in μMT mice with KRasG12D-PDEC lesions expressed less of TAM-like CD206 and, correspondingly, more of M1-like CD86 on their cell surface. This observation suggested that absence of B cells prevents (or reverses) pro-tumorigenic macrophage polarization in pancreatic cancer towards a more anti-tumorigenic macrophage phenotype. After a more detailed analysis of B cell subtypes, we found that a regulatory subtype of B cells (Bregs, as defined by CD19+CD1dhighCD5+ surface phenotype and IL-10 expression) is specifically expanded in pancreata of KC and orthotopically grafted animals. Correspondingly, we find that a proportion of CD20+ B cells that infiltrate human PanIN lesions express IL-10. Reconstitution of μMT mice with B regulatory cells rescued the in vivo KRasG12D-PDEC growth defect.

Conclusion: These results identify a novel mode of immunomodulation in pancreatic neoplasia and suggest that regulatory B cells may have an important role in promoting pro-tumorigenic immune responses.

Citation Format: Yuliya Pylayeva-Gupta, Jesse S. Handler, Cristina Hajdu, Dafna Bar-Sagi. The role of B regulatory cells in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B62.