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Macrophage PI3Kγ Drives Pancreatic Ductal Adenocarcinoma Progression
Megan M Kaneda1, Paola Cappello2, Abraham V Nguyen1
1Moores Cancer Center, University of California, San Diego, La Jolla, California.
Unlabelled:
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.
Insights
Targeting PI3Kγ in pancreatic cancer reprograms immunosuppressive macrophages to enhance anti-tumor immunity. This approach improves survival and chemotherapy response in preclinical models, offering a new therapeutic strategy for pancreatic ductal adenocarcinoma.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, necessitating novel therapeutic strategies.
- Current treatments offer limited survival benefits, highlighting the need for innovative approaches like immunotherapy.
Purpose of the Study:
- To investigate the role of PI3Kγ in regulating the tumor microenvironment in PDAC.
- To evaluate the therapeutic potential of PI3Kγ inhibition in PDAC models.
Main Methods:
- Utilized animal models of PDAC.
- Investigated the effects of genetic and pharmacologic PI3Kγ inhibition.
- Assessed changes in macrophage programming, immune responses, tumor invasion, and desmoplasia.
Main Results:
- PI3Kγ drives immunosuppressive transcriptional programming in tumor-associated macrophages.
- Inhibition of PI3Kγ reprograms macrophages to promote CD8(+) T-cell-mediated anti-tumor immunity.
- PI3Kγ blockade reduces tumor cell invasion, metastasis, and desmoplasia.
- Targeting PI3Kγ enhances responsiveness to standard-of-care chemotherapy.
Conclusions:
- Macrophage PI3Kγ is a critical regulator of PDAC progression.
- Pharmacologic inhibition of PI3Kγ is a promising new therapeutic modality for PDAC.
- Targeting PI3Kγ restores anti-tumor immune responses and improves treatment efficacy.
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