Bruton Tyrosine Kinase-Dependent Immune Cell Cross-talk Drives Pancreas Cancer
| Autor: | Gunderson, Andrew J, Kaneda, Megan M, Tsujikawa, Takahiro, Nguyen, Abraham V, Affara, Nesrine I, Ruffell, Brian, Gorjestani, Sara, Liudahl, Shannon M, Truitt, Morgan, Olson, Peter, Kim, Grace, Hanahan, Douglas, Tempero, Margaret A, Sheppard, Brett, Irving, Bryan, Chang, Betty Y, Varner, Judith A, Coussens, Lisa M |
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| Rok vydání: | 2016 |
| Předmět: |
IgG
Knockout Oncology and Carcinogenesis Cell Communication Cell Line Mice Pancreatic Cancer Rare Diseases Receptors Leukocytes Agammaglobulinaemia Tyrosine Kinase Animals Humans Class Ib Phosphatidylinositol 3-Kinase Myeloid Cells Cancer B-Lymphocytes Tumor Animal Macrophages Carcinoma Macrophage Activation Protein-Tyrosine Kinases Pancreatic Neoplasms Orphan Drug Pancreatic Ductal Immune System Disease Models Disease Progression Digestive Diseases Biomarkers Signal Transduction |
| Zdroj: | Cancer discovery, vol 6, iss 3 |
| Popis: | UnlabelledPancreas 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 T(H)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(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.SignificanceWe 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. |
| Databáze: | OpenAIRE |
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