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Tumor microenvironment of Pancreatic Cancer

Discrepancies in the Tumor Microenvironment of Spontaneous and Orthotopic Murine Models of Pancreatic Cancer Uncover a New Immunostimulatory Phenotype for B Cells

While studying B cells in pancreatic cancer, we noticed an important discrepancy between human data, which suggest B cells contribute to the anti-tumor response, and mouse data, which indicate an immunosuppressive, protumorigenic role. Most of the murine data, however, derives from orthotopic models, in which a pancreatic-cell line is injected in the pancreas of healthy mice and tumors develop rapidly. In order to clarify this discrepancy, we assessed B-cell infiltrates from orthotopics and a genetic mouse model, the KPC mouse, in which tumors develop spontaneously in the course of several months, due to overexpression of mutated KRAS and P53 in pancreatic cells. Our data showed that orthotopic tumors have no immune-cell infiltrate, while KPC tumors do, better mimicking human cancers. Furthermore, infiltrating B cells present a very different phenotype from B cells residing in the spleen and lymph-nodes, showing signs of activation and differentiation, as well as expression of immune-stimulatory factors. Indeed, depletion of B cells with anti-CD20 treatment in KPC mice, did not cause a decrease in tumor growth. As B-cell infiltration correlated with T-cell and DC infiltration, we hypothesize that B cells infiltrating pancreatic tumors contribute to the adaptive anti-tumor response and therefore have tumor suppressing roles. However, B cells residing in secondary lymphoid organs have a different, possibly more immunosuppressive phenotype. Our results indicate that strategies to increase tumor infiltration by immune cells could be beneficial in the treatment of this dismal disease.


Publication

https://pubmed.ncbi.nlm.nih.gov/30972056/


Contact

Dr. Melania Capasso

DZNE

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