Prognostic Perspectives of STING and PD-L1 Expression and Correlation with the Prognosis of Epstein-Barr Virus-Associated Gastric Cancers
0
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Background/Aims: Epstein-Barr virus-associated gastric cancers (EBVaGCs) have unique molecular and clinicopathological characteristics. The cyclic GMP-AMP synthase-stimulator of interferon genes (STING) pathway is recently recognized as the critical innate immunity against pathogens and tumors. STING is also a master regulator in the cancer-immunity cycle and targeting STING could synergize with existing immune-checkpoint therapies. However, the role of STING in GC, especially in EBVaGC, and its correlation with programmed death-ligand 1 (PD-L1) remain largely unclear. Methods: We collected 78 cases of EBVaGCs and 210 cases of EBV-negative GC (EBVnGC) from a total of 1,443 cases of GC analyzed by EBV-encoded small RNA in situ hybridization. We investigated STING and PD-L1 expression and their concomitant prognostic value in EBVaGCs and EBVnGCs using tissue microarray and immunohistochemistry. The effects of STING and PD-L1 expression on the overall survival of patients with EBVaGC or EBVnGC were assessed by univariate and multivariate analysis. Results: We found that both STING and PD-L1 exhibited significantly higher expression in the EBVaGCs than that in the EBVnGCs. The expression of STING was positively correlated with that of PD-L1 in EBVaGCs. Simultaneous negative expression of STING and PD-L1, and positive expression of STING were independent prognostic risk factors for EBVaGC and EBVnGC, respectively. Conclusions: This is the first prognostic retrospective study of STING and PD-L1 expression and the prognosis among EBVaGC and EBVnGC. The expression and prognostic value of STING and PD-L1 are different in the two types of GCs. STING and PD-L1 are promising prognostic biomarkers and therapeutic targets for EBVaGC and EBVnGC.
Abstract
Background/Aims: Epstein-Barr virus-associated gastric cancers (EBVaGCs) have unique molecular and clinicopathological characteristics. The cyclic GMP-AMP synthase-stimulator of interferon genes (STING) pathway is recently recognized as the critical innate immunity against pathogens and tumors. STING is also a master regulator in the cancer-immunity cycle and targeting STING could synergize with existing immune-checkpoint therapies. However, the role of STING in GC, especially in EBVaGC, and its correlation with programmed death-ligand 1 (PD-L1) remain largely unclear. Methods: We collected 78 cases of EBVaGCs and 210 cases of EBV-negative GC (EBVnGC) from a total of 1,443 cases of GC analyzed by EBV-encoded small RNA in situ hybridization. We investigated STING and PD-L1 expression and their concomitant prognostic value in EBVaGCs and EBVnGCs using tissue microarray and immunohistochemistry. The effects of STING and PD-L1 expression on the overall survival of patients with EBVaGC or EBVnGC were assessed by univariate and multivariate analysis. Results: We found that both STING and PD-L1 exhibited significantly higher expression in the EBVaGCs than that in the EBVnGCs. The expression of STING was positively correlated with that of PD-L1 in EBVaGCs. Simultaneous negative expression of STING and PD-L1, and positive expression of STING were independent prognostic risk factors for EBVaGC and EBVnGC, respectively. Conclusions: This is the first prognostic retrospective study of STING and PD-L1 expression and the prognosis among EBVaGC and EBVnGC. The expression and prognostic value of STING and PD-L1 are different in the two types of GCs. STING and PD-L1 are promising prognostic biomarkers and therapeutic targets for EBVaGC and EBVnGC.
참고문헌 (56)
- Sung H, "Global Cancer Statistics 2020 : GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries", CA Cancer J Clin, 71, pp.209~249 (2021)
- Wu MS, "Epstein-Barr virus-associated gastric carcinomas : relation to H. pylori infection and genetic alterations", Gastroenterology, 118, pp.1031~1038 (2000)
- Song HJ, "Host inflammatory response predicts survival of patients with Epstein-Barr virusassociated gastric carcinoma", Gastroenterology, 139, pp.84~92 (2010)
- Morales-Sanchez A, "Epstein-Barr virus-associated gastric cancer and potential mechanisms of oncogenesis", Curr Cancer Drug Targets, 17, pp.534~554 (2017)
- Murphy G, "Metaanalysis shows that prevalence of Epstein-Barr virus-positive gastric cancer differs based on sex and anatomic location", Gastroenterology, 137, pp.824~833 (2009)
- Pyo JS, "Clinicopathological features and prognostic implication of gastric carcinoma with lymphoid stroma", Gastroenterol Res Pract, 2020, pp.6628412~ (2020)
- Carneiro F, "WHO classification of tumours of the digestive system", pp.85~95 (2019), International Agency for Research on Cancer
- Cancer Genome Atlas Research Network, "Comprehensive molecular characterization of gastric adenocarcinoma", Nature, 513, pp.202~209 (2014)
- Lipson EJ, "Antagonists of PD-1 and PD-L1 in cancer treatment", Semin Oncol, 42, pp.587~600 (2015)
- Gu L, "PD-L1 and gastric cancer prognosis : a systematic review and meta-analysis", PLoS One, 12, pp.e0182692~ (2017)
- Kim ST, "Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer", Nat Med, 24, pp.1449~1458 (2018)
- Xie T, "Positive status of Epstein-Barr virus as a biomarker for gastric cancer immunotherapy : a prospective observational study", J Immunother, 43, pp.139~144 (2020)
- Liu S, "Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3activation", Science, 347, pp.aaa2630~ (2015)
- Corrales L, "The host STING pathway at the interface of cancer and immunity", J Clin Invest, 126, pp.2404~2411 (2016)
- Ishikawa H, "STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity", Nature, 461, pp.788~792 (2009)
- Xia T, "Recurrent loss of STING signaling in melanoma correlates with susceptibility to viral oncolysis", Cancer Res, 76, pp.6747~6759 (2016)
- Xia T, "Deregulation of STING signaling in colorectal carcinoma constrains DNA damage responses and correlates with tumorigenesis", Cell Rep, 14, pp.282~297 (2016)
- Kitajima S, "Suppression of STING associated with LKB1 loss in KRAS-driven lung cancer", Cancer Discov, 9, pp.34~45 (2019)
- Song S, "Decreased expression of STING predicts poor prognosis in patients with gastric cancer", Sci Rep, 7, pp.39858~ (2017)
- Miao L, "Targeting the STING pathway in tumor-associated macrophages regulates innate immune sensing of gastric cancer cells", Theranostics, 10, pp.498~515 (2020)
- Li A, "Activating cGASSTING pathway for the optimal effect of cancer immunotherapy", J Hematol Oncol, 12, pp.35~ (2019)
- Zhu Y, "STING : a master regulator in the cancer-immunity cycle", Mol Cancer, 18, pp.152~ (2019)
- Jaffer AA, "AJCC cancer staging manual", pp.203~220 (2016), Springer
- Jin S, "The PD-1, PD-L1 expression and CD3+ T cell infiltration in relation to outcome in advanced gastric signet-ring cell carcinoma, representing a potential biomarker for immunotherapy", Oncotarget, 8, pp.38850~38862 (2017)
- Kulangara K, "Clinical utility of the combined positive score for programmed death ligand-1expression and the approval of pembrolizumab for treatment of gastric cancer", Arch Pathol Lab Med, 143, pp.330~337 (2019)
- Yang J, "Epstein-Barr virusassociated gastric cancer : a distinct subtype", Cancer Lett, 495, pp.191~199 (2020)
- Fang WL, "The clinicopathological features and genetic alterations in Epstein-Barr virusassociated gastric cancer patients after curative surgery", Cancers(Basel), 12, pp.1517~ (2020)
- Ojima H, "Infrequent overexpression of p53 protein in Epstein-Barr virus-associated gastric carcinomas", Jpn J Cancer Res, 88, pp.262~266 (1997)
- Kang BW, "Prognostic value of tumorinfiltrating lymphocytes in Epstein-Barr virus-associated gastric cancer", Ann Oncol, 27, pp.494~501 (2016)
- Camargo MC, "Improved survival of gastric cancer with tumour Epstein-Barr virus positivity : an international pooled analysis", Gut, 63, pp.236~243 (2014)
- Ma J, "Differentiated tumor immune microenvironment of Epstein-Barr virus-associated and negative gastric cancer : implication in prognosis and immunotherapy", Oncotarget, 8, pp.67094~67103 (2017)
- Choi E, "Prognostic perspectives of PD-L1 combined with tumor-infiltrating lymphocytes, Epstein-Barr virus, and microsatellite instability in gastric carcinomas", Diagn Pathol, 15, pp.69~ (2020)
- Fuchs CS, "Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer : phase 2 clinical KEYNOTE-059 trial", JAMA Oncol, 4, pp.e180013~ (2018)
- Wang F, "Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD-1 antibody in phase Ib", II clinical trial NCT02915432, 2019, pp.30, 1479~1486
- Seo AN, "Intratumoural PD-L1expression is associated with worse survival of patients with Epstein-Barr virus-associated gastric cancer", Br J Cancer, 117, pp.1753~1760 (2017)
- Cho J, "Four distinct immune microenvironment subtypes in gastric adenocarcinoma with special reference to microsatellite instability", ESMO Open, 3, pp.e000326~ (2018)
- Dong M, "Expression and prognostic roles of PIK3CA, JAK2, PD-L1, and PD-L2 in Epstein-Barr virus-associated gastric carcinoma", Hum Pathol, 53, pp.25~34 (2016)
- Saito R, "Overexpression and gene amplification of PD-L1 in cancer cells and PD-L1+ immune cells in Epstein-Barr virusassociated gastric cancer : the prognostic implications", Mod Pathol, 30, pp.427~439 (2017)
- Sundar R, "Transcriptional analysis of immune genes in Epstein-Barr virus-associated gastric cancer and association with clinical outcomes", Gastric Cancer, 21, pp.1064~1070 (2018)
- Yoon CJ, "Epstein-Barr virusencoded miR-BART5-5p upregulates PD-L1 through PIAS3", pSTAT3 modulation, worsening clinical outcomes of PD-L1-positive gastric carcinomas, 2020, pp.23, 780~795
- Derks S, "Abundant PD-L1expression in Epstein-Barr Virus-infected gastric cancers", Oncotarget, 7, pp.32925~32932 (2016)
- Kim DH, "Clinical significance of tumor and immune cell PD-L1 expression in gastric adenocarcinoma", In Vivo, 34, pp.3171~3180 (2020)
- Wu Y, "PD-1 and PD-L1 co-expression predicts favorable prognosis in gastric cancer", Oncotarget, 8, pp.64066~64082 (2017)
- Kawazoe A, "Clinicopathological features of programmed death ligand 1 expression with tumor-infiltrating lymphocyte, mismatch repair, and Epstein-Barr virus status in a large cohort of gastric cancer patients", Gastric Cancer, 20, pp.407~415 (2017)
- Koemans WJ, "Beyond the PD-L1 horizon : in search for a good biomarker to predict success of immunotherapy in gastric and esophageal adenocarcinoma", Cancer Lett, 442, pp.279~286 (2019)
- Diskin B, "PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer", Nat Immunol, 21, pp.442~454 (2020)
- Pulko V, "B7-h1 expressed by activated CD8 T cells is essential for their survival", J Immunol, 187, pp.5606~5614 (2011)
- Xing J, "TRIM29 promotes DNA virus infections by inhibiting innate immune response", Nat Commun, 8, pp.945~ (2017)
- He L, "STING signaling in tumorigenesis and cancer therapy : a friend or foe", Cancer Lett, 402, pp.203~212 (2017)
- Sen T, "Targeting DNA damage response promotes antitumor immunity through STINGmediated T-cell activation in small cell lung cancer", Cancer Discov, 9, pp.646~661 (2019)
- Wang H, "cGAS is essential for the antitumor effect of immune checkpoint blockade", Proc Natl Acad Sci U S A, 114, pp.1637~1642 (2017)
- Wilson DR, "Biodegradable STING agonist nanoparticles for enhanced cancer immunotherapy", Nanomedicine, 14, pp.237~246 (2018)
- Liang D, "Activated STING enhances Tregs infiltration in the HPV-related carcinogenesis of tongue squamous cells via the c-jun", CCL22 signal, 2015, pp.1852, 2494~2503
- Lemos H, "STING promotes the growth of tumors characterized by low antigenicity via IDO activation", Cancer Res, 76, pp.2076~2081 (2016)
- Lohard S, "STING-dependent paracriny shapes apoptotic priming of breast tumors in response to anti-mitotic treatment", Nat Commun, 11, pp.259~ (2020)
- Wang C, "Reproducibility of PD-L1 immunohistochemistry interpretation across various types of genitourinary and head", neck carcinomas, antibody clones, and tissue types, 2018, pp.82, 131~139