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

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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.

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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

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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).

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Authors and Affiliations

  1. Department of Pathology, Seoul National University Bundang Hospital, Gumi-ro 173, 82 Beon-gil, Bundang-gu, Seongnam-Si, Gyeonggi-do, 13620, Republic of Korea

    Yujun Park & Hye Seung Lee

  2. Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, Republic of Korea

    Yujun Park, Woo Ho Kim & Hye Seung Lee

  3. Department of Pathology, Seoul National University Hospital, 100 Daehak-ro, Jongno-gu, Seoul, Republic of Korea

    Jiwon Koh, Yoonjin Kwak & Woo Ho Kim

  4. Department of Surgery, Seoul National University Bundang Hospital, Gumi-ro 173, 82 Beon-gil, Bundang-gu, Seongnam-Si, Gyeonggi-do, Republic of Korea

    Sang-Hoon Ahn, Do Joong Park & Hyung-Ho Kim

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  1. Yujun Park
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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.

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Correspondence to Hye Seung Lee.

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The authors report no conflict of interest.

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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).

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

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Park, Y., Koh, J., Kwak, Y. et al. Clinicopathologic significance of human leukocyte antigen class I expression in patients with stage II and III gastric cancer. Cancer Immunol Immunother 68, 1779–1790 (2019). https://doi.org/10.1007/s00262-019-02410-z

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