PI3Kγ inhibition combined with DNA vaccination unleashes a B-cell-dependent antitumor immunity that hampers pancreatic cancer

Phosphoinositide-3-kinase gamma (PI3K gamma) plays a critical role in pancreatic ductal adenocarcinoma (PDA) by driving the recruitment of myeloid-derived suppressor cells (MDSC) into tumor tissues, leading to tumor growth and metastasis. MDSC also impair the efficacy of immunotherapy. In this study we verify the hypothesis that MDSC targeting, via PI3K gamma inhibition, synergizes with alpha-enolase (ENO1) DNA vaccination in counteracting tumor growth.Mice that received ENO1 vaccination followed by PI3K gamma inhibition had significantly smaller tumors compared to those treated with ENO1 alone or the control group, and correlated with i) increased circulating anti-ENO1 specific IgG and IFN gamma secretion by T cells, ii) increased tumor infiltration of CD8+ T cells and M1-like macrophages, as well as up-modulation of T cell activation and M1-like related transcripts, iii) decreased infiltration of Treg FoxP3+ T cells, endothelial cells and pericytes, and down-modulation of the stromal compartment and T cell exhaustion gene transcription, iv) reduction of mature and neo-formed vessels, v) increased follicular helper T cell activation and vi) increased "antigen spreading", as many other tumor-associated antigens were recognized by IgG2c "cytotoxic" antibodies. PDA mouse models genetically devoid of PI3K gamma showed an increased survival and a pattern of transcripts in the tumor area similar to that of pharmacologically-inhibited PI3K gamma-proficient mice. Notably, tumor reduction was abrogated in ENO1 + PI3K gamma inhibition-treated mice in which B cells were depleted.These data highlight a novel role of PI3K gamma in B cell-dependent immunity, suggesting that PI3K gamma depletion strengthens the anti-tumor response elicited by the ENO1 DNA vaccine.