title: Immune checkpoint proteins PD-1 and TIM-3 are both highly expressed in liver tissues and correlate with their gene polymorphisms in patients with HBV-related hepatocellular carcinoma.
abstract: Immune checkpoint proteins programmed death-1 (PD-1) and T-cell immunoglobulin domain and mucin domain containing molecule-3 (TIM-3) expression and their gene polymorphisms have separately been shown to be associated with hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study simultaneously examined PD-1 and TIM-3 expression in liver tissues and PD1 and TIM3 polymorphisms and analyzed their correlations in 171 patients with HBV-related HCC and 34 patients with HBV-related cirrhosis.PD-1 and TIM-3 expression in liver tissues were examined by immunohistochemistry and the genotypes of PD1 rs10204525 and TIM3 rs10053538 polymorphisms were determined using genomic DNA extracted from peripheral blood as template.Both PD-1 and TIM-3 expressions in liver infiltrating lymphocytes of HCC tumor tissues were significantly higher than those in tumor adjacent tissues or cirrhotic tissues. The elevated PD-1 and TIM-3 expressions were significantly associated with higher tumor grades. The levels between PD-1 and TIM-3 expression in tumor tissues and tumor adjacent tissues had a significant positive intercorrelation. The expressions of PD-1 and TIM-3 in tumor tissues, tumor adjacent tissues, and cirrhotic tissues were significantly associated with PD1 and TIM3 polymorphisms, with genotype AA of PD1 rs10204525 and genotypes GT+TT of TIM3 rs10053538 being associated with significantly increased PD-1 and TIM-3 expression, respectively.These findings support the potential to improve the efficiency of immune checkpoint-targeted therapy and reduce resistance to the therapy by blocking both PD-1 and TIM-3 and suggest the potential to apply the genotype determination of PD1 rs10204525 and TIM3 rs10053538 as biomarkers of immune checkpoint-directed therapies.
authors.affiliation: Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University Department of Infectious Diseases, Yanan University Affiliated Hospital, Yanan Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi' an, Shaanxi, China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Li
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Zhou
authors.forename: Jiao
authors.initials: J
authors.lastname: Sang
authors.forename: Yanping
authors.initials: Y
authors.lastname: Chen
authors.forename: Qunying
authors.initials: Q
authors.lastname: Han
authors.forename: Yi
authors.initials: Y
authors.lastname: Lv
authors.forename: Zhengwen
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000328:Adult; D006528:Carcinoma, Hepatocellular / Q000737:chemistry* / Q000235:genetics / Q000473:pathology*; D005260:Female; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000032:analysis* / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000150:complications; D006801:Humans; D008099:Liver / Q000737:chemistry; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology*; D008214:Lymphocytes / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D011110:Polymorphism, Genetic; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis* / Q000235:genetics
chemical_list: C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor