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Cancer Discov. 2016 Aug;6(8):870-85. doi: 10.1158/2159-8290.CD-15-1346. Epub 2016 May 13.

Macrophage PI3Kγ Drives Pancreatic Ductal Adenocarcinoma Progression.

Author information

1
Moores Cancer Center, University of California, San Diego, La Jolla, California.
2
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.
3
Moores Cancer Center, University of California, San Diego, La Jolla, California. Department of Pathology, Mudanjiang Medical University, Mudanjiang, China.
4
Moores Cancer Center, University of California, San Diego, La Jolla, California. Department of Surgery, University of California, San Diego, La Jolla, California.
5
Moores Cancer Center, University of California, San Diego, La Jolla, California. Department of Pathology, University of California, San Diego, La Jolla, California.
6
Center for Computational Biology and Bioinformatics, University of California, San Diego, La Jolla, California.
7
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.
8
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.
9
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.

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.

SIGNIFICANCE:

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.

PMID:
27179037
PMCID:
PMC5091937
DOI:
10.1158/2159-8290.CD-15-1346
[Indexed for MEDLINE]
Free PMC Article

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