title: Bruton Tyrosine Kinase-Dependent Immune Cell Cross-talk Drives Pancreas Cancer.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gunderson
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Kaneda
authors.affiliation: 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.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tsujikawa
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Abraham V
authors.initials: AV
authors.lastname: Nguyen
authors.affiliation: Department of Pathology, University of California, San Francisco, California.
authors.forename: Nesrine I
authors.initials: NI
authors.lastname: Affara
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon.
authors.forename: Brian
authors.initials: B
authors.lastname: Ruffell
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Sara
authors.initials: S
authors.lastname: Gorjestani
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Liudahl
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, California.
authors.forename: Morgan
authors.initials: M
authors.lastname: Truitt
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, California.
authors.forename: Peter
authors.initials: P
authors.lastname: Olson
authors.affiliation: Department of Pathology, University of California, San Francisco, California. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Grace
authors.initials: G
authors.lastname: Kim
authors.affiliation: Swiss Institute for Experimental Cancer Research, Swiss Federal Institute of Technology, Lausanne, Switzerland.
authors.forename: Douglas
authors.initials: D
authors.lastname: Hanahan
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California. Department of Medicine, University of California, San Francisco, California.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Tempero
authors.affiliation: Department of Surgery, Oregon Health and Science University, Portland, Oregon. Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
authors.forename: Brett
authors.initials: B
authors.lastname: Sheppard
authors.affiliation: Genentech, South San Francisco, California.
authors.forename: Bryan
authors.initials: B
authors.lastname: Irving
authors.affiliation: Pharmacyclics Inc., Sunnyvale, California.
authors.forename: Betty Y
authors.initials: BY
authors.lastname: Chang
authors.affiliation: 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.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Varner
authors.affiliation: 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.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Coussens
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology*; D045744:Cell Line, Tumor; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D007107:Immune System / Q000166:cytology* / Q000473:pathology*; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; D017452:Receptors, IgG; D058544:Class Ib Phosphatidylinositol 3-Kinase; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse