Editors' ChoiceCancer Immunology

B cells fuel pancreatic cancer

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Science Signaling  05 Apr 2016:
Vol. 9, Issue 422, pp. ec77
DOI: 10.1126/scisignal.aaf8036

Immune cells can eradicate tumor cells, but tumors or conditions in the tumor microenvironment often suppress immune cell activity; thus, immunotherapies may be effective for many cancers. Characteristics of aggressive pancreatic ductal adenocarcinoma (PDAC) include a stage-wise inflammatory progression and an abundant infiltration by leukocytes of both lymphoid and myeloid origin. Three studies now describe how B cells contribute to PDAC (see also Roghanian et al.). Using mouse models of PDAC, Gunderson et al. found that B cells promoted macrophage polarization to an immunosuppressive phenotype. Coculture chamber assays indicated that this effect in macrophages was mediated by B cell–derived molecules released by the activation of Bruton’s tyrosine kinase (BTK) in B cells. B cell–derived immunoglobulin (Ig)–containing complexes can activate the Ig-γ receptor (FcγR) in macrophages, which then induces BTK-mediated integrin signaling downstream of the p110γ subunit of phosphatidylinositol 3-kinase (PI3Kγ) in macrophages, which promotes their recruitment out of the circulation and into tumors. The authors found that treating mice with either the BTK inhibitor ibrutinib or a PI3Kγ inhibitor restored the antitumor activity of cytotoxic T cells, suppressed PDAC growth, and improved the responsiveness of mice to the chemotherapeutic gemcitabine. In exploring the role of FcγR activation of macrophages in B cell–dependent tumor growth, Pylayeva-Gupta et al. did not see an increase in Ig production by B cells that infiltrated orthotopic PDAC xenografts in mice. Using B cell adoptive transfer technology, they instead found that the growth of KRAS-mutant PDAC in mice was dependent on B cells that produced interleukin-35 (IL-35), a cytokine that is associated with some autoimmune diseases and is increased in the sera of patients with pancreatic cancer. The authors also found that treating mice with a blocking antibody against CXCL13, a chemokine secreted by stromal fibroblasts, inhibited the recruitment of B cells into orthotopic PDAC tumors. Hypoxia is another characteristic of aggressive PDAC, but the correlation between PDAC progression in patients and the abundance of hypoxia-inducible factor 1α (HIF-1α) is inconsistent. Also using mouse models and human samples of KRAS-mutant PDAC, Lee et al. found that although the abundance of HIF-1α is increased during the early stages of pancreatic neoplasia, deletion of HIF-1α unexpectedly accelerated PDAC development. This was because loss of HIF-1α resulted in the increased abundance of CXCL13 in the tumor microenvironment, which recruited B cells into the pancreas. Treating mice with B cell–depleting antibodies inhibited the progression of pancreatic intraepithelial neoplasia (PanIN) in mice. Together, these studies highlight the importance of B cells in the tumor microenvironment and reveal potential new targets for therapeutic intervention.

A. J. Gunderson, M. M. Kaneda, T. Tsujikawa, A. V. Nguyen, N. I. Affara, B. Ruffell, S. Gorjestani, S. M. Liudahl, M. Truitt, P. Olson, G. Kim, D. Hanahan, M. A. Tempero, B. Sheppard, B. Irving, B. Y. Chang, J. A. Varner, L. M. Coussens, Bruton tyrosine kinase–dependent immune cell cross-talk drives pancreas cancer. Cancer Discov. 6, 270–285 (2016). [PubMed]

Y. Pylayeva-Gupta, S. Das, J. S. Handler, C. H. Hajdu, M. Coffre, S. B. Koralov, D. Bar-Sagi, IL35-producing B cells promote the development of pancreatic neoplasia. Cancer Discov. 6, 247–255 (2016). [PubMed]

K. E. Lee, M. Spata, L. J. Bayne, E. L. Buza, A. C. Durham, D. Allman, R. H. Vonderheide, M. C. Simon, Hif1α deletion reveals pro-neoplastic function of B cells in pancreatic neoplasia. Cancer Discov. 6, 256–269 (2016). [PubMed]

A. Roghanian, C. Fraser , M. Kleyman, J. Chen, B cells promote pancreatic tumorigenesis. Cancer Discov. 6, 230–232 (2016). [PubMed]

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