PACSIN1 promotes immunosuppression in gastric cancer by degrading MHC-I  

作　　者：Zhu Liu Xin Li Ali Muhammad Qiannan Sun Qi Zhang Yang Wang Yong Wang Jun Ren Daorong Wang 

机构地区：[1]The Yangzhou School of Clinical Medicine of Nanjing Medical University,Yangzhou 225001,China [2]Clinical Medical College,Yangzhou University,Yangzhou 225001,China [3]Northern Jiangsu People’s Hospital,Yangzhou 225001,China [4]General Surgery Institute of Yangzhou,Yangzhou University,Yangzhou 225001,China [5]Yangzhou Key Laboratory of Basic and Clinical Transformation of Digestive and Metabolic Diseases,Yangzhou 225001,China [6]Department of Pharmacy,Clinical Medical College,Yangzhou University,Northern Jiangsu People’s Hospital,Yangzhou 225001,China

出　　处：《Acta Biochimica et Biophysica Sinica》2024年第10期1473-1482,共10页生物化学与生物物理学报（英文版）

基　　金：supported by the grant from the Yangzhou Key Laboratory of Basic and Clinical Transformation of Digestive and Metabolic Diseases(No.YZ2020159).

摘　　要：Gastric cancer(GC)is a common gastrointestinal system malignancy.PACSIN1 functions as an oncogene in various cancers.This study aims to investigate the potential of PACSIN1 as a target in GC treatment.Gene expression is determined by RT-qPCR,immunofluorescence staining,and immunohistochemistry assay.FISH is performed to determine the colocalization of PACSIN1 and the major histocompatibility complex(MHC-I).Cytokine release and cell functions are analyzed by flow cytometry.In vivo assays are also conducted.Histological analysis is performed using H&E staining.The results show that PACSIN1 is overexpressed in GC patients,especially in those with immunologically-cold tumors.A high level of PACSIN1 is associated with poor prognosis.PACSIN1 deficiency inhibits autophagy but increases antigen presentation in GC cells.Moreover,PACSIN1 deficiency inhibits the lysosomal fusion and selective autophagy of MHC-I,increases CD8^(+)T-cell infiltration,and suppresses tumor growth and liver metastasis in vivo.Additionally,PACSIN1 knockout enhances the chemosensitivity of cells to immune checkpoint blockade.In summary,PACSIN1 mediates lysosomal fusion and selective autophagy of MHC-I and suppresses antigen presentation and CD8^(+)T-cell infiltration,thus inhibiting antitumor immunity in GC.

关 键 词：gastric cancer PACSIN1 AUTOPHAGY MHC-I CD8^(+)T cell 

分 类 号：R730.3[医药卫生—肿瘤]