期刊
CANCER DISCOVERY
卷 6, 期 3, 页码 270-285出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-15-0827
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资金
- NCI/NIH [R01CA167426, R01CA126820, R01CA083133, R01CA130980, R01CA140943, R01CA15531, U54CA163123]
- Department of Defense Breast Cancer Research Program [W81XWH-11-1-0702]
- Susan G. Komen Foundation [KG110560, KG111084]
- Brenden-Colson Center for Pancreatic Health
- Stand Up To Cancer-Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant [SU2C-AACR-DT14-14]
- [T32AI078903-04]
- [T32HL098062]
- [T32CA009523]
- [T32CA121938]
- [R01CA167426-03S1]
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 FcR gamma(+) tumor-associated macrophages, resulting in T(H)2-type macrophage programming via BTK activation in a PI3K gamma-dependent manner. Treatment of PDAC-bearing mice with the BTK inhibitor PCI32765 (ibrutinib) or by PI3K gamma inhibition reprogrammed macrophages toward a T(H)1 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. (C) 2015 AACR.
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