title: Macrophage PI3Kγ Drives Pancreatic Ductal Adenocarcinoma Progression.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a low 5-year survival rate, yet new immunotherapeutic modalities may offer hope for this and other intractable cancers. Here, we report that inhibitory targeting of PI3Kγ, a key macrophage lipid kinase, stimulates antitumor immune responses, leading to improved survival and responsiveness to standard-of-care chemotherapy in animal models of PDAC. PI3Kγ selectively drives immunosuppressive transcriptional programming in macrophages that inhibits adaptive immune responses and promotes tumor cell invasion and desmoplasia in PDAC. Blockade of PI3Kγ in PDAC-bearing mice reprograms tumor-associated macrophages to stimulate CD8(+) T-cell-mediated tumor suppression and to inhibit tumor cell invasion, metastasis, and desmoplasia. These data indicate the central role that macrophage PI3Kγ plays in PDAC progression and demonstrate that pharmacologic inhibition of PI3Kγ represents a new therapeutic modality for this devastating tumor type.
  
  
  
  We report here that PI3Kγ regulates macrophage transcriptional programming, leading to T-cell suppression, desmoplasia, and metastasis in pancreas adenocarcinoma. Genetic or pharmacologic inhibition of PI3Kγ restores antitumor immune responses and improves responsiveness to standard-of-care chemotherapy. PI3Kγ represents a new therapeutic immune target for pancreas cancer. Cancer Discov; 6(8); 870-85. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 803.
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: Center for Experimental Research and Medical Studies (CeRMS), Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Cappello
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: Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Natacha
authors.initials: N
authors.lastname: Ralainirina
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Chanae R
authors.initials: CR
authors.lastname: Hardamon
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Philippe
authors.initials: P
authors.lastname: Foubert
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Schmid
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California. Department of Pathology, Mudanjiang Medical University, Mudanjiang, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Sun
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Evangeline
authors.initials: E
authors.lastname: Mose
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California. Department of Surgery, University of California, San Diego, La Jolla, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Bouvet
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California. Department of Surgery, University of California, San Diego, La Jolla, California.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lowy
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California. Department of Pathology, University of California, San Diego, La Jolla, California.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Valasek
authors.affiliation: Center for Computational Biology and Bioinformatics, University of California, San Diego, La Jolla, California.
authors.forename: Roman
authors.initials: R
authors.lastname: Sasik
authors.affiliation: Center for Experimental Research and Medical Studies (CeRMS), Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. jvarner@ucsd.edu franco.novelli@unito.it emilio.hirsch@unito.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Novelli
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Molecular Biotechnology Center, Torino, Italy. jvarner@ucsd.edu franco.novelli@unito.it emilio.hirsch@unito.it.
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California. Department of Pathology, University of California, San Diego, La Jolla, California. jvarner@ucsd.edu franco.novelli@unito.it emilio.hirsch@unito.it.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Varner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015415:Biomarkers; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D055786:Gene Knockout Techniques; D064593:Heterografts; D006801:Humans; D056747:Immunomodulation; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009026:Mortality; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D010636:Phenols / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C539252:3-(2,4-diamino-6-(3-hydroxyphenyl)pteridin-7-yl)phenol; D000970:Antineoplastic Agents; D015415:Biomarkers; D010636:Phenols; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor; D011621:Pteridines; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human