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Cancer Immunology, Immunotherapy

, Volume 68, Issue 11, pp 1779–1790 | Cite as

Clinicopathologic significance of human leukocyte antigen class I expression in patients with stage II and III gastric cancer

  • Yujun Park
  • Jiwon Koh
  • Yoonjin Kwak
  • Sang-Hoon Ahn
  • Do Joong Park
  • Hyung-Ho Kim
  • Woo Ho Kim
  • Hye Seung LeeEmail author
Original Article

Abstract

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.

Keywords

Gastric cancer Human leukocyte antigen Beta-2-microglobulin Programmed death-ligand 1 Biomarkers 

Abbreviations

AJCC

American Joint Committee on Cancer

β2M

Beta-2-microglobulin

CPS

Combined positive score

EBER

Epstein–Barr virus-encoded small RNA

EBV

Epstein–Barr virus

FFPE

Formalin-fixed paraffin-embedded

GC

Gastric cancer

HLA I

Human leukocyte antigen class I

IRB

Institutional review board

ISH

In situ hybridization

MSI-H

Microsatellite instability-high

MSI-L

Microsatellite instability-low

MSI

Microsatellite instability

MSS

Microsatellite stable

NCI

National Cancer Institute

TIL

Tumor-infiltrating lymphocyte

TMA

Tissue microarray

Notes

Author contributions

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.

Funding

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).

Informed consent

Written patient consent and the consent process were waived by the IRB under the condition of anonymization and no additional intervention to the participants.

Supplementary material

262_2019_2410_MOESM1_ESM.pdf (424 kb)
Supplementary material 1 (PDF 424 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PathologySeoul National University Bundang HospitalSeongnam-SiRepublic of Korea
  2. 2.Department of PathologySeoul National University College of MedicineSeoulRepublic of Korea
  3. 3.Department of PathologySeoul National University HospitalSeoulRepublic of Korea
  4. 4.Department of SurgerySeoul National University Bundang HospitalSeongnam-SiRepublic of Korea

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