Macrophage PI3Kγ drives pancreatic ductal adenocarcinoma progression

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a low five-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 anti-tumor 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 pharmacological inhibition of PI3Kγ represents a new therapeutic modality for this devastating tumor type.