Authors: 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
Summary:
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.
Source:
Cancer Discovery; 2015, 6 (3): 270