Journal Article

A CXCR4 partial agonist improves immunotherapy by targeting polymorphonuclear myeloid-derived suppressor cells and cancer-driven granulopoiesis

White, Ruth A, Zamechek, Leah B, Lederman, Seth, Ochiai, Yosuke, Wang, Timothy C, Wu, Feijing, Waterbury, Quin T, Daugherty, Bruce, Tu, Ruhong, Hu, Lucas ZhongMing, Han, Arnold S, Harle, David W, Qian, Jin, Zheng, Hualong, Kobayashi, Hiroki, Zhi, Xiaofei, Zeng, Yi, Moon, Christine S, LaBella, Jonathan S, Moy, Ryan H, Ma, Chenkai, Zheng, Biyun

2024

Overview

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are pathologically activated neutrophils that potently impair immunotherapy responses. The chemokine receptor CXCR4, a central regulator of hematopoiesis, represents an attractive PMN-MDSC target1. Here, we fused a secreted CXCR4 partial agonist TFF2 to mouse serum albumin (MSA) and demonstrated that TFF2-MSA peptide synergized with anti-PD-1 to induce tumor regression or eradication, inhibited distant metastases, and prolonged survival in multiple gastric cancer (GC) models. Using histidine decarboxylase (Hdc)-GFP transgenic mice to track PMN-MDSC , we found TFF2-MSA selectively reduced the immunosuppressive Hdc-GFP CXCR4 tumor PMN-MDSCs while preserving proinflammatory neutrophils, thereby boosting CD8 T cell-mediated anti-tumor response together with anti-PD-1. Furthermore, TFF2-MSA systemically reduced PMN-MDSCs and bone marrow granulopoiesis. In contrast, CXCR4 antagonism plus anti-PD-1 failed to provide a similar therapeutic benefit. In GC patients, expanded PMN-MDSCs containing a prominent CXCR4 LOX-1 subset are inversely correlated with the TFF2 level and CD8 T cells in circulation. Collectively, our studies introduce a strategy of using CXCR4 partial agonism to restore anti-PD-1 sensitivity in GC by targeting PMN-MDSCs and granulopoiesis.

• Publisher: Cold Spring Harbor Laboratory
• Subject: Cancer Biology