GLP1 alleviates oleic acid-propelled lipocalin-2 generation by tumor-infiltrating CD8(+) T cells to reduce polymorphonuclear MDSC recruitment and enhances viral immunotherapy in pancreatic cancer.

Recruitment of polymorphonuclear MDSCs (PMN-MDSCs) in the TME suppresses the antitumor activity of tumor-infiltrating CD8(+) T cells (CD8(+) TILs). Little is known about the role of antitumoral CD8(+) TILs in actively initiating an immune-tolerant microenvironment, particularly in the recruitment of PMN-MDSCs. In this study, we found that immunotherapy-activated CD8(+) TILs significantly increased PNM-MDSC infiltration in the TME, resulting in antitumor resistance. When CD8(+) T cells are activated, lipocalin-2 (LCN2) expression is strongly upregulated, which significantly enhances PMN-MDSC chemotaxis. Mechanistically, immune activation increased fatty acid synthesis in CD8(+) T cells, particularly oleic acid (OA), which induced lysosomal membrane permeabilization, releasing cathepsin B and subsequently activating NF-κB to promote LCN2 expression. Moreover, we showed that glucagon-like peptide 1 (GLP1) effectively inhibited OA synthesis in activated CD8(+) T cells, reducing LCN2 production. We then developed a recombinant adenovirus encoding GLP1 (AdV-GLP1), which significantly reduced PMN-MDSC infiltration and reinvigorated the antitumor activity of CD8(+) TILs. In various pancreatic cancer models, including subcutaneous, orthotopic, and humanized CDX/PDX models, AdV-GLP1 displayed excellent antitumor efficacy. Our work advances the understanding of how immunotherapy-activated CD8(+) TILs initiate PMN-MDSC infiltration and provides a clinically relevant strategy to target this interaction and improve cancer immunotherapy.