Data from Bruton Tyrosine Kinase–Dependent Immune Cell Cross-talk Drives Pancreas Cancer

<div>Abstract<p>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<sup>+</sup> tumor–associated macrophages, resulting in T<sub>H</sub>2-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 T<sub>H</sub>1 phenotype that fostered CD8<sup>+</sup> 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.</p><p><b>Significance:</b> 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. <i>Cancer Discov; 6(3); 270–85. ©2015 AACR</i>.</p><p><i>See related commentary by Roghanian et al., p. 230</i>.</p><p><i>See related article by Pylayeva-Gupta et al., p. 247</i>.</p><p><i>See related article by Lee et al., p. 256</i>.</p><p>This article is highlighted in the In This Issue feature, p. 217</p></div>