Bruton tyrosine kinase–Dependent immune cell cross-talk drives pancreas cancer

Andrew J. Gunderson, Megan M. Kaneda, Takahiro Tsujikawa, Abraham V. Nguyen, Nesrine I. Affara, Brian Ruffell, Sara Gorjestani, Shannon M. Liudahl, Morgan Truit, Peter Olson, Grace Kim, Douglas Hanahan, Margaret A. Tempero, Brett Sheppard, Bryan Irving, Betty Y. Chang, Judith A. Varner, Lisa M. Coussens

Research output: Contribution to journalArticle

189 Scopus citations

Abstract

Pancreas ductal adenocarcinoma (PDAC) has one of the worst 5-year survival rates of all solid tumors, and thus new treatment strategies are urgently needed. Here, we report that targeting Bruton tyrosine kinase (BTK), a key B-cell and macrophage kinase, restores T cell– dependent antitumor immune responses, thereby inhibiting PDAC growth and improving responsiveness to standard-of-care chemotherapy. We report that PDAC tumor growth depends on cross-talk between B cells and FcRγ+ tumor–associated macrophages, resulting in TH2-type macrophage programming via BTK activation in a PI3Kγ-dependent manner. Treatment of PDAC-bearing mice with the BTK inhibitor PCI32765 (ibrutinib) or by PI3Kγ inhibition reprogrammed macrophages toward a TH1 phenotype that fostered CD8+ T-cell cytotoxicity, and suppressed PDAC growth, indicating that BTK signaling mediates PDAC immunosuppression. These data indicate that pharmacologic inhibition of BTK in PDAC can reactivate adaptive immune responses, presenting a new therapeutic modality for this devastating tumor type. SIGNIFICANCE: We report that BTK regulates B-cell and macrophage-mediated T-cell suppression in pancreas adenocarcinomas. Inhibition of BTK with the FDA-approved inhibitor ibrutinib restores T cell–dependent antitumor immune responses to inhibit PDAC growth and improves responsiveness to chemotherapy, presenting a new therapeutic modality for pancreas cancer.

Original languageEnglish (US)
Pages (from-to)270-285
Number of pages16
JournalCancer discovery
Volume6
Issue number3
DOIs
StatePublished - Mar 2016

ASJC Scopus subject areas

  • Oncology

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    Gunderson, A. J., Kaneda, M. M., Tsujikawa, T., Nguyen, A. V., Affara, N. I., Ruffell, B., Gorjestani, S., Liudahl, S. M., Truit, M., Olson, P., Kim, G., Hanahan, D., Tempero, M. A., Sheppard, B., Irving, B., Chang, B. Y., Varner, J. A., & Coussens, L. M. (2016). Bruton tyrosine kinase–Dependent immune cell cross-talk drives pancreas cancer. Cancer discovery, 6(3), 270-285. https://doi.org/10.1158/2159-8290.CD-15-0827