Clinicopathologic significance of human leukocyte antigen class I expression in patients with stage II and III gastric cancer
Human leukocyte antigen class I (HLA I) molecules composed of alpha (heavy) chain, including HLA-A, -B, or -C encoded by HLA genes, and beta-2-microglobulin (β2M) are membrane proteins on all nucleated cells that display peptide antigens for recognition by CD8-positive cytotoxic T cells. Here, we examined the clinicopathologic signification of HLA I expression in patients with gastric cancer (GC). Immunohistochemistry was performed to detect HLA A/B/C, β2M, CD8, p53, and programmed death-ligand 1 (PD-L1) in the center and invasive margin of the tumor in 395 stage II and III GCs using tissue array method. Additionally, Epstein–Barr virus (EBV) infection and microsatellite instability (MSI) status were investigated. Negative expression of HLA A/B/C and β2M was observed in 258 (65.3%) and 235 (59.5%) of 395 stage II and III GCs, respectively. Negative HLA I expression was significantly associated with aggressive clinicopathologic features. Furthermore, negative expression of HLA A/B/C and β2M was inversely correlated with CD8-positive cytotoxic T cell infiltration, EBV-positivity, and PD-L1 expression (all p < 0.001). Patients with HLA A/B/C-negative GC had worse overall survival (OS) (p = 0.019) and combined analysis with both HLA A/B/C and β2M expression status significantly predicted OS in univariate (p = 0.004) and multivariate survival analysis (p = 0.016). Negative expression of HLA A/B/C and β2M was frequently observed in stage II and III GCs, particularly with the aggressive clinicopathologic features, and correlated with an unfavorable prognosis and host immune response status. These findings contribute to further development of immunotherapy.
KeywordsGastric cancer Human leukocyte antigen Beta-2-microglobulin Programmed death-ligand 1 Biomarkers
American Joint Committee on Cancer
Combined positive score
Epstein–Barr virus-encoded small RNA
- HLA I
Human leukocyte antigen class I
Institutional review board
In situ hybridization
National Cancer Institute
YP and HSL conceived and designed the study. SHA, DJP, and HHK provided clinical data and interpretation. YP, JK, YK, WHK, and HSL collected, analyzed, and interpreted pathologic data. YP and HSL wrote the manuscript. All the authors read and approved the final manuscript.
This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2016R1D1A1B03931744).
Compliance with ethical standards
Conflict of interest
The authors report no conflict of interest.
Ethical approval and ethical standards
All human tissue samples were obtained from the archive of the Department of Pathology, Seoul National University Bundang Hospital and clinicopathologic data including patients’ survival were obtained from medical records. This study was approved by the institutional review board (IRB) of Seoul National University Bundang Hospital (IRB number: B-1606/349-308 and B-1402/240-004).
Written patient consent and the consent process were waived by the IRB under the condition of anonymization and no additional intervention to the participants.
- 1.Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386. https://doi.org/10.1002/ijc.29210 CrossRefPubMedPubMedCentralGoogle Scholar
- 4.Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, Nashimoto A, Fujii M, Nakajima T, Ohashi Y (2011) Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol 29(33):4387–4393. https://doi.org/10.1200/JCO.2011.36.5908 CrossRefGoogle Scholar
- 5.Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T et al (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet (Lond, Engl) 376(9742):687–697. https://doi.org/10.1016/S0140-6736(10)61121-X CrossRefGoogle Scholar
- 7.Cabrera T, Lara E, Romero JM, Maleno I, Real LM, Ruiz-Cabello F, Valero P, Camacho FM, Garrido F (2007) HLA class I expression in metastatic melanoma correlates with tumor development during autologous vaccination. Cancer Immunol Immunother 56(5):709–717. https://doi.org/10.1007/s00262-006-0226-7 CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Carretero R, Romero JM, Ruiz-Cabello F, Maleno I, Rodriguez F, Camacho FM, Real LM, Garrido F, Cabrera T (2008) Analysis of HLA class I expression in progressing and regressing metastatic melanoma lesions after immunotherapy. Immunogenetics 60(8):439–447. https://doi.org/10.1007/s00251-008-0303-5 CrossRefGoogle Scholar
- 11.Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL et al (2010) Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 28(19):3167–3175. https://doi.org/10.1200/JCO.2009.26.7609 CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454. https://doi.org/10.1056/NEJMoa1200690 CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Muro K, Chung HC, Shankaran V, Geva R, Catenacci D, Gupta S, Eder JP, Golan T, Le DT, Burtness B et al (2016) Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol 17(6):717–726. https://doi.org/10.1016/S1470-2045(16)00175-3 CrossRefGoogle Scholar
- 14.Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, Chen L, Pardoll DM, Topalian SL, Anders RA (2014) Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 20(19):5064–5074. https://doi.org/10.1158/1078-0432.CCR-13-3271 CrossRefPubMedPubMedCentralGoogle Scholar
- 17.del Campo AB, Kyte JA, Carretero J, Zinchencko S, Mendez R, Gonzalez-Aseguinolaza G, Ruiz-Cabello F, Aamdal S, Gaudernack G, Garrido F et al (2014) Immune escape of cancer cells with beta2-microglobulin loss over the course of metastatic melanoma. Int J Cancer 134(1):102–113. https://doi.org/10.1002/ijc.28338 CrossRefGoogle Scholar
- 20.Koh J, Ock CY, Kim JW, Nam SK, Kwak Y, Yun S, Ahn SH, Park DJ, Kim HH, Kim WH et al (2017) Clinicopathologic implications of immune classification by PD-L1 expression and CD8-positive tumor-infiltrating lymphocytes in stage II and III gastric cancer patients. Oncotarget 8(16):26356–26367. https://doi.org/10.18632/oncotarget.15465 CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Shitara K, Ozguroglu M, Bang YJ, Di Bartolomeo M, Mandala M, Ryu MH, Fornaro L, Olesinski T, Caglevic C, Chung HC et al (2018) Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet (Lond, Engl) 392(10142):123–133. https://doi.org/10.1016/S0140-6736(18)31257-1 CrossRefGoogle Scholar
- 23.Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges JP et al (2018) 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(5):e180013. https://doi.org/10.1001/jamaoncol.2018.0013 CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Shen YQ, Zhang JQ, Miao FQ, Zhang JM, Jiang Q, Chen H, Shan XN, Xie W (2005) Relationship between the downregulation of HLA class I antigen and clinicopathological significance in gastric cancer. World J Gastroenterol 11(23):3628–3631. https://doi.org/10.3748/wjg.v11.i23.3628 CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Ferron A, Perez-Ayala M, Concha A, Cabrera T, Redondo M, Oliva MR, Ruiz-Cabello F, Garrido F (1989) MHC class I and II antigens on gastric carcinomas and autologous mucosa. J Immunogenet 16(4–5):413–423. https://doi.org/10.1111/j.1744-313X.1989.tb00489.x CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Hanagiri T, Shigematsu Y, Shinohara S, Takenaka M, Oka S, Chikaishi Y, Nagata Y, Baba T, Uramoto H, So T et al (2013) Clinical significance of expression of cancer/testis antigen and down-regulation of HLA class-I in patients with stage I non-small cell lung cancer. Anticancer Res 33(5):2123–2128Google Scholar
- 34.Watson NF, Ramage JM, Madjd Z, Spendlove I, Ellis IO, Scholefield JH, Durrant LG (2006) Immunosurveillance is active in colorectal cancer as downregulation but not complete loss of MHC class I expression correlates with a poor prognosis. Int J Cancer 118(1):6–10. https://doi.org/10.1002/ijc.21303 CrossRefGoogle Scholar
- 35.Ogino T, Shigyo H, Ishii H, Katayama A, Miyokawa N, Harabuchi Y, Ferrone S (2006) HLA class I antigen down-regulation in primary laryngeal squamous cell carcinoma lesions as a poor prognostic marker. Cancer Res 66(18):9281–9289. https://doi.org/10.1158/0008-5472.CAN-06-0488 CrossRefPubMedPubMedCentralGoogle Scholar
- 36.Goeppert B, Frauenschuh L, Zucknick M, Roessler S, Mehrabi A, Hafezi M, Stenzinger A, Warth A, Pathil A, Renner M et al (2015) Major histocompatibility complex class I expression impacts on patient survival and type and density of immune cells in biliary tract cancer. Br J Cancer 113(9):1343–1349. https://doi.org/10.1038/bjc.2015.337 CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Homma I, Kitamura H, Torigoe T, Tanaka T, Sato E, Hirohashi Y, Masumori N, Sato N, Tsukamoto T (2009) Human leukocyte antigen class I down-regulation in muscle-invasive bladder cancer: its association with clinical characteristics and survival after cystectomy. Cancer Sci 100(12):2331–2334. https://doi.org/10.1111/j.1349-7006.2009.01329.x CrossRefPubMedPubMedCentralGoogle Scholar
- 40.Redondo M, Concha A, Oldiviela R, Cueto A, Gonzalez A, Garrido F, Ruiz-Cabello F (1991) Expression of HLA class I and II antigens in bronchogenic carcinomas: its relationship to cellular DNA content and clinical-pathological parameters. Cancer Res 51(18):4948–4954Google Scholar
- 42.Perea F, Sanchez-Palencia A, Gomez-Morales M, Bernal M, Concha A, Garcia MM, Gonzalez-Ramirez AR, Kerick M, Martin J, Garrido F et al (2018) HLA class I loss and PD-L1 expression in lung cancer: impact on T-cell infiltration and immune escape. Oncotarget 9(3):4120–4133. https://doi.org/10.18632/oncotarget.23469 CrossRefGoogle Scholar
- 44.Kim ST, Cristescu R, Bass AJ, Kim KM, Odegaard JI, Kim K, Liu XQ, Sher X, Jung H, Lee M et al (2018) Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med 24(9):1449–1458. https://doi.org/10.1038/s41591-018-0101-z CrossRefPubMedPubMedCentralGoogle Scholar
- 47.Kasajima A, Sers C, Sasano H, Johrens K, Stenzinger A, Noske A, Buckendahl AC, Darb-Esfahani S, Muller BM, Budczies J et al (2010) Down-regulation of the antigen processing machinery is linked to a loss of inflammatory response in colorectal cancer. Hum Pathol 41(12):1758–1769. https://doi.org/10.1016/j.humpath.2010.05.014 CrossRefPubMedPubMedCentralGoogle Scholar
- 49.Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V et al (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528):568–571. https://doi.org/10.1038/nature13954 CrossRefPubMedPubMedCentralGoogle Scholar