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Supplementary Figure 2 from Macrophage PI3Kγ Drives Pancreatic Ductal Adenocarcinoma Progression

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posted on 2023-04-03, 21:01 authored by Megan M. Kaneda, Paola Cappello, Abraham V. Nguyen, Natacha Ralainirina, Chanae R. Hardamon, Philippe Foubert, Michael C. Schmid, Ping Sun, Evangeline Mose, Michael Bouvet, Andrew M. Lowy, Mark A. Valasek, Roman Sasik, Francesco Novelli, Emilio Hirsch, Judith A. Varner

Effect of PI3Kγ inhibition on immune cell populations.

Funding

Ministero della Salute Ricerca Sanitaria Finalizzata

Associazione Italiana Ricerca sul Cancro

University of Turin-Progetti Ateneo 2014-Compagnia di San Paolo

NCI/NIH

Lustgarten Foundation, and AACR

History

ARTICLE 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

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