Qian and Ma et al. fused TFF2, a partial CXCR4 agonist, with murine serum albumin (MSA) to develop TFF2–MSA peptides that restore anti-PD-1 sensitivity in syngeneic gastric cancer (GC) tumor models. TFF2-MSA distinctly modulated CXCR4 signaling, reducing bone marrow granulopoiesis compared to full agonists. TFF2–MSA selectively reduced PMN-MDSCs in the TME, promoted CD8+ T cell responses, and sensitized tumors to anti-PD-1. TFF2–MSA showed superior antitumor efficacy over existing PMN-targeted strategies. Reduced levels of plasma TFF2 correlated with elevated CXCR4+LOX-1+ neutrophils in patients with GC.
Contributed by Shishir Pant
ABSTRACT: 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(+)CXCR4(high) 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.
Author Info: (1) Division of Digestive and Liver Diseases, Department of Medicine and Herbert Irving Comprehensive Cancer Research Center, Columbia University Medical Center, New York, NY 10032
Author Info: (1) 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. (2) Integrated Diagnostic, Human Health, Health and Biosecurity, CSIRO, Westmead, NSW 2070, Australia. (3) 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. (4) 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; Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China. (5) 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; Department of Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA. (6) 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; Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China. (7) 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. (8) 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. (9) 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; Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China. (10) 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. (11) 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. (12) 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. (13) Division of Hematology and Medical Oncology, NYU Langone's Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY 10016, USA. (14) 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. (15) 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. (16) 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. (17) Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA. (18) Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA. (19) Department of Microbiology and Immunology, Columbia University, New York, NY 10032, USA. (20) Tonix Pharmaceuticals, Inc., Chatham, NJ 07928, USA. (21) Tonix Pharmaceuticals, Inc., Chatham, NJ 07928, USA. (22) 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; Columbia University Digestive and Liver Diseases Research Center, Columbia University, New York, NY 10032, USA. Electronic address: tcw21@cumc.columbia.edu.
