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EnglishPancreatic 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.
| Titolo: | Macrophage PI3Kγ drives pancreatic ductal adenocarcinoma progression | |
| Autori Riconosciuti: | ||
| Autori: | Kaneda MM; Cappello P; Nguyen AV; Ralainirina N; Hardamon CR; Foubert P; Schmid MC; Sun P; Mose E; Bouvet M; Lowy AM; Valasek MA; Sasik R; Novelli F; Hirsch E; Varner JA | |
| Data di pubblicazione: | 2016 | |
| 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. | |
| Volume: | 6 | |
| Fascicolo: | 8 | |
| Pagina iniziale: | 870 | |
| Pagina finale: | 885 | |
| Digital Object Identifier (DOI): | 10.1158/2159-8290.CD-15-1346 | |
| Rivista: | CANCER DISCOVERY | |
| Appare nelle tipologie: | 03A-Articolo su Rivista |
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| File | Descrizione | Tipologia | Licenza | |
|---|---|---|---|---|
| pre-print Kaneda_Cancer Discovery_2016.pdf | POSTPRINT (VERSIONE FINALE DELL’AUTORE) | Open Access Visualizza/Apri | ||
| Kaneda et al_Cancer Discovery_2016.pdf | PDF EDITORIALE | Utenti riconosciuti Richiedi una copia |
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