Zhang et al. identified sialic acid-bearing IgG (SIA-IgG) in PDAC cells, which correlated positively with immunosuppressive (IS) TAM infiltration, and negatively with survival. SIA-IgG potently induced IS TAMs via sialic acid binding to Siglecs 7/9/10, which upregulated CD206, ARG1, and M2-like cytokines in TAMs. In a positive feedback loop, TAM-derived TGFβ promoted SIA-IgG secretion in cancer cells by enhancing the IgG heavy chain and sialyltransferase ST6GAL1. An anti-SIA-IgG mAb was effective in s.c. and orthotopic PDAC models, including PDX and T cell-deficient tumors, inhibited IS-TAM infiltration, and increased CD8+ T cell infiltration.
Contributed by Morgan Janes
ABSTRACT: The limited effectiveness of T cell-based immune checkpoint blockade (ICB) therapy in most patients with pancreatic ductal adenocarcinoma (PDAC) is largely due to poor CD8(+) T cell infiltration and a highly immunosuppressive microenvironment driven by excessive myeloid cell accumulation. This highlights the urgent need for new immunotherapy targets and strategies. In this study, an identified pro-cancer factor, cancer cell-derived sialylated IgG (SIA-IgG), is found to be significantly overexpressed in pancreatic cancer cells. SIA-IgG inhibits macrophage phagocytosis and induces an M2-like immunosuppressive phenotype through interactions with Siglec-7/9/10. SIA-IgG and TGF-_1, a key immunosuppressive factor, reinforce each other in a positive feedback loop, promoting immune evasion in PDAC. Blocking SIA-IgG with specific monoclonal antibodies shows significant therapeutic potential through reversal of PDAC's immunosuppressive microenvironment. Our findings identify the SIA-IgG/Siglec axis as an immunotherapeutic target for PDAC, offering a feasible approach for the development of immunotherapeutic strategies.
Author Info: (1) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 10019
Author Info: (1) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China. (2) Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. Electronic address: cuiming@pumch.cn. (3) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China; Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing 210031, China. (4) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China. (5) Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. (6) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China. (7) Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. (8) Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. (9) State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Research Center for Molecular Pathology, Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. (10) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China. (11) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China. (12) Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. (13) Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. Electronic address: zhao8028@263.net. (14) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China. Electronic address: qiuxy@bjmu.edu.cn.
