Macrophage PI3Kγ drives pancreatic ductal adenocarcinoma progression



Schmid, MC ORCID: 0000-0002-3445-0013
(2016) Macrophage PI3Kγ drives pancreatic ductal adenocarcinoma progression. Cancer Discovery, 6 (8). pp. 870-885.

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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.

Item Type: Article
Uncontrolled Keywords: Cell Line, Tumor, Macrophages, Animals, Mice, Transgenic, Mice, Knockout, Humans, Mice, Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms, Neoplasm Metastasis, Disease Models, Animal, Disease Progression, Phenols, Pteridines, Platelet-Derived Growth Factor, Antineoplastic Agents, Mortality, Xenograft Model Antitumor Assays, Cell Movement, Macrophage Activation, Gene Expression, Male, Gene Knockout Techniques, Immunomodulation, Class Ib Phosphatidylinositol 3-Kinase, Heterografts, Biomarkers, Phosphoinositide-3 Kinase Inhibitors
Depositing User: Symplectic Admin
Date Deposited: 13 Jul 2016 09:05
Last Modified: 19 Jan 2023 07:34
DOI: 10.1158/2159-8290.CD-15-1346
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3002271