PD-L1 restrains PD-1+Nrp1lo Treg cells to suppress inflammation-driven colorectal tumorigenesis
Dakota B. Poschel,
John D. Klement,
Alyssa D. Merting,
Chunwan Lu,
Yang Zhao,
Dafeng Yang,
Wei Xiao,
Huabin Zhu,
Ponnala Rajeshwari,
Michael Toscano,
Kimya Jones,
Amanda Barrett,
Roni J. Bollag,
Padraic G. Fallon,
Huidong Shi,
Kebin Liu
Affiliations
Dakota B. Poschel
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
John D. Klement
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
Alyssa D. Merting
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
Chunwan Lu
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA
Yang Zhao
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA
Dafeng Yang
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
Wei Xiao
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
Huabin Zhu
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
Ponnala Rajeshwari
Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
Michael Toscano
Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
Kimya Jones
Department of Pathology, Medical College of Georgia, Augusta, GA 30912, USA
Amanda Barrett
Department of Pathology, Medical College of Georgia, Augusta, GA 30912, USA
Roni J. Bollag
Department of Pathology, Medical College of Georgia, Augusta, GA 30912, USA
Padraic G. Fallon
Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin, Dublin, Ireland
Huidong Shi
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta, GA 30912, USA; Corresponding author
Kebin Liu
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA; Corresponding author
Summary: T cells function not only as an essential component of host cancer immunosurveillance but also as a regulator of colonic inflammation, a process that promotes colorectal cancer. Programmed death-ligand 1 (PD-L1) is a T cell-negative regulator, but its role in regulation of T cell functions in the context of colorectal cancer is unknown. We report that global deletion of Cd274 results in increased colonic inflammation, PD-1+ T cells, and inflammation-driven colorectal tumorigenesis in mice. Single-cell RNA sequencing (scRNA-seq) analysis revealed that PD-L1 suppresses subpopulations of programmed cell death protein 1 (PD-1)+Nrp1lo regulatory T (Treg) cells and interleukin (IL) 6+ neutrophils in colorectal tumor. Treg cells produce transforming growth factor (TGF) β to recruit IL6+ neutrophils. Neutrophils produce IL6 to inhibit activation of tumor-specific cytotoxic T lymphocytes (CTLs) and primary CTLs. Accordingly, IL6 blockade immunotherapy increases CTL activation and suppresses colon tumor growth in vivo. Our findings determine that PD-L1 restrains PD-1+Nrp1loTGFβ+ Treg cells to suppress IL6+ neutrophil tumor recruitment to sustain CTL activation to control inflammation-driven colorectal tumorigenesis.
