Bruton Tyrosine Kinase-Dependent Immune Cell Cross-talk Drives Pancreas Cancer.
- Gunderson AJ Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon.
- Kaneda MM Moores Cancer Center, University of California, San Diego, La Jolla, California.
- Tsujikawa T Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon. Department of Otolaryngology-Head and Neck Surgery, Oregon Health and Science University, Portland, Oregon.
- Nguyen AV Moores Cancer Center, University of California, San Diego, La Jolla, California.
- Affara NI Department of Pathology, University of California, San Francisco, California.
- Ruffell B Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon.
- Gorjestani S Moores Cancer Center, University of California, San Diego, La Jolla, California.
- Liudahl SM Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon.
- Truitt M Department of Biochemistry and Biophysics, University of California, San Francisco, California.
- Olson P Department of Biochemistry and Biophysics, University of California, San Francisco, California.
- Kim G Department of Pathology, University of California, San Francisco, California. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
- Hanahan D Swiss Institute for Experimental Cancer Research, Swiss Federal Institute of Technology, Lausanne, Switzerland.
- Tempero MA Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California. Department of Medicine, University of California, San Francisco, California.
- Sheppard B Department of Surgery, Oregon Health and Science University, Portland, Oregon. Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
- Irving B Genentech, South San Francisco, California.
- Chang BY Pharmacyclics Inc., Sunnyvale, California.
- Varner JA Moores Cancer Center, University of California, San Diego, La Jolla, California. Department of Pathology, University of California, San Diego, La Jolla, California. coussenl@ohsu.edu jvarner@ucsd.edu.
- Coussens LM Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon. Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. coussenl@ohsu.edu jvarner@ucsd.edu.
- 2015-12-31
Published in:
- Cancer discovery. - 2016
Agammaglobulinaemia Tyrosine Kinase
Animals
B-Lymphocytes
Biomarkers
Carcinoma, Pancreatic Ductal
Cell Communication
Cell Line, Tumor
Class Ib Phosphatidylinositol 3-Kinase
Disease Models, Animal
Disease Progression
Humans
Immune System
Leukocytes
Macrophage Activation
Macrophages
Mice
Mice, Knockout
Myeloid Cells
Pancreatic Neoplasms
Protein-Tyrosine Kinases
Receptors, IgG
Signal Transduction
English
UNLABELLED
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 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.
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.
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 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.
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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1158/2159-8290.CD-15-0827
- PMID 26715645
- Persistent URL
- https://sonar.ch/global/documents/176932
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