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.

PMN-MDSCs; Tumor immunotherapy; fatty acid; glucagon-like peptide 1; lipocalin 2.