Qian Jin, Ma Chenkai, Waterbury Quin T, Zhi Xiaofei, Moon Christine S, Tu Ruhong, Kobayashi Hiroki, Wu Feijing, Zheng Biyun, Zeng Yi, Zheng Hualong, Ochiai Yosuke, White Ruth A, Harle David W, LaBella Jonathan S, Zamechek Leah B, ZhongMing Hu Lucas, Moy Ryan H, Han Arnold S, Daugherty Bruce L, Lederman Seth, Wang Timothy C
Division of Digestive and Liver Diseases, Department of Medicine and Herbert Irving Comprehensive Cancer Research Center, Columbia University Medical Center, New York, NY 10032, USA.
Integrated Diagnostic, Human Health, Health and Biosecurity, CSIRO, Westmead, NSW 2070, Australia.
Cancer Cell. 2025 Jun 21. doi: 10.1016/j.ccell.2025.06.006.
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-GFPCXCR4 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 CXCR4LOX-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.
病理激活的免疫抑制性中性粒细胞会损害癌症免疫治疗的疗效。趋化因子受体CXCR4作为造血和中性粒细胞生物学的核心调节因子，是一个颇具吸引力的靶点。在此，我们将分泌型CXCR4部分激动剂三叶因子2（TFF2）与小鼠血清白蛋白（MSA）融合，并证明TFF2-MSA肽与抗PD-1协同作用可抑制原发性肿瘤生长和远处转移，并延长胃癌（GC）小鼠模型的生存期。利用组氨酸脱羧酶（Hdc）-绿色荧光蛋白（GFP）转基因小鼠在体内追踪多形核骨髓来源的抑制性细胞（PMN-MDSC），我们发现TFF2-MSA可选择性减少Hdc-GFP CXCR4免疫抑制性中性粒细胞，从而增强抗PD-1介导的CD8 T细胞对肿瘤的杀伤作用。重要的是，TFF2-MSA可减少骨髓粒细胞生成，这与未能带来治疗益处的CXCR4拮抗作用形成对比。在GC患者中，CXCR4 LOX-1低密度中性粒细胞升高与循环TFF2水平降低相关。总体而言，我们的研究引入了一种策略，即利用CXCR4部分激动作用，通过靶向免疫抑制性中性粒细胞和粒细胞生成来恢复抗PD-1敏感性。
