2025-10-10 コロンビア大学
<関連情報>
- https://www.cancer.columbia.edu/news/immune-altering-drug-hits-cancer-stomach
- https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00256-9
CXCR4部分作動薬は免疫抑制性好中球と癌誘導性顆粒球新生を標的とすることで免疫療法を改善する A CXCR4 partial agonist improves immunotherapy by targeting immunosuppressive neutrophils and cancer-driven granulopoiesis
Jin Qian ∙ Chenkai Ma ∙ Quin T. Waterbury ∙ … ∙ Bruce L. Daugherty ∙ Seth Lederman ∙ Timothy C. Wang
Cancer Cell Published:June 26, 2025
DOI:https://doi.org/10.1016/j.ccell.2025.06.006
Graphical abstract
Highlights
- TFF2-MSA, a CXCR4 partial agonist, sensitizes mouse gastric cancer to anti-PD-1
- TFF2-MSA reduces immunosuppressive neutrophils and cancer-driven granulopoiesis
- TFF2-MSA plus anti-PD-1 induces robust anti-tumoral CD8+ T cell responses
- TFF2 reduction correlates with elevated PMN-MDSCs in gastric cancer patients
Summary
Pathologically activated immunosuppressive neutrophils impair cancer immunotherapy efficacy. The chemokine receptor CXCR4, a central regulator of hematopoiesis and neutrophil biology, represents an attractive target. Here, we fuse a secreted CXCR4 partial agonist, trefoil factor 2 (TFF2), to mouse serum albumin (MSA) and demonstrate that TFF2-MSA peptide synergizes with anti-PD-1 to inhibit primary tumor growth and distant metastases and prolongs survival in gastric cancer (GC) mouse models. Using histidine decarboxylase (Hdc)-GFP transgenic mice to track polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) in vivo, we find that TFF2-MSA selectively reduces the Hdc-GFP+CXCR4high immunosuppressive neutrophils, thereby boosting CD8+ T cell-mediated tumor killing with anti-PD-1. Importantly, TFF2-MSA reduces bone marrow granulopoiesis, contrasting with CXCR4 antagonism, which fails to confer therapeutic benefits. In GC patients, elevated CXCR4+LOX-1+ low-density neutrophils correlate with lower circulating TFF2 levels. Collectively, our studies introduce a strategy that utilizes CXCR4 partial agonism to restore anti-PD-1 sensitivity by targeting immunosuppressive neutrophils and granulopoiesis.
