title: UPR decreases CD226 ligand CD155 expression and sensitivity to NK cell-mediated cytotoxicity in hepatoma cells.
abstract: NK cells play important roles in anti-tumor immunity. CD226 is a major NK-cell activating receptor, which transduces activating signals after binding ligands CD155 and CD112. Here, we demonstrated that activated unfolded protein response (UPR) attenuated the sensitivity of human hepatocellular carcinoma cell (HCC) to NK-cell cytotoxicity by decreasing the expression level of CD226 ligand CD155 in HCC. The decreased expression level of CD155 was due to the involvement of the activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1α (IRE1α) pathways. In addition, the IRE1α pathway contributed to the increased expression level of the ER-associated degradation (ERAD)-related molecule HRD1 and facilitated the degradation of CD155. Moreover, we found that low levels of CD155 expression were significantly associated with poor prognosis in patients with HCC. Thus, our results provide molecular, cellular, and clinical evidence demonstrating a novel NK cell-associated immune evasion mechanism, and indicate that targeting this immune evasion pathway may be meaningful in treating patients with HCC.
authors.affiliation: Department of Immunology, the Fourth Military Medical University, Xi'an, Shaanxi, China; No. 150 Central Hospital of PLA, Luoyang, Henan, China.
authors.forename: Jiuyu
authors.initials: J
authors.lastname: Gong
authors.forename: Liang
authors.initials: L
authors.lastname: Fang
authors.forename: Rongrong
authors.initials: R
authors.lastname: Liu
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Jinliang
authors.initials: J
authors.lastname: Xing
authors.forename: Yibing
authors.initials: Y
authors.lastname: Chen
authors.forename: Ran
authors.initials: R
authors.lastname: Zhuang
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Chunmei
authors.initials: C
authors.lastname: Zhang
authors.forename: Angang
authors.initials: A
authors.lastname: Yang
authors.forename: Xudong
authors.initials: X
authors.lastname: Zhang
authors.forename: Boquan
authors.initials: B
authors.lastname: Jin
authors.forename: Lihua
authors.initials: L
authors.lastname: Chen
mesh_terms: D051702:Activating Transcription Factor 6 / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000473:pathology; D060746:Endoplasmic Reticulum-Associated Degradation / Q000276:immunology*; D004722:Endoribonucleases / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D056945:Hep G2 Cells; D006801:Humans; D007111:Immunity, Cellular; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D008113:Liver Neoplasms / Q000276:immunology* / Q000473:pathology; D009363:Neoplasm Proteins / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000276:immunology; D011991:Receptors, Virus / Q000276:immunology*; D019139:Tumor Escape; D044767:Ubiquitin-Protein Ligases / Q000276:immunology; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D009363:Neoplasm Proteins; D011991:Receptors, Virus; C066100:poliovirus receptor; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases
keywords: Cancer; Immune evasion; NK cells