Advertisement

Gastric Cancer

, Volume 21, Issue 6, pp 1064–1070 | Cite as

Transcriptional analysis of immune genes in Epstein–Barr virus-associated gastric cancer and association with clinical outcomes

  • Raghav Sundar
  • Aditi Qamra
  • Angie Lay Keng Tan
  • Shenli Zhang
  • Cedric Chuan Young Ng
  • Bin Tean Teh
  • Jeeyun Lee
  • Kyoung-Mee Kim
  • Patrick Tan
Short Communication

Abstract

Background

Epstein–Barr virus-associated gastric cancer (EBVaGC) has traditionally been associated with high expression of PD-L1 and immune infiltration. Correlations between PD-L1 and other immune-related gene (IRG) expressions in EBVaGC have not been previously described.

Methods

We performed NanoString® transcriptomic profiling and PD-L1 immunohistochemistry (IHC) (using the FDA approved Dako PD-L1 IHC 22C3) on EBVaGC samples from gastric cancer patients undergoing primary tumor resections at Samsung Medical Centre, South Korea. For controls, EBV-negative samples from the previously reported Asian Cancer Research Group (EBVnegACRG) cohort were used. Genes tested included PD-L1 and other IRGs related to intra-tumoral cytolytic activity, cytokines and immune checkpoints. Samples with PD-L1 expression > 34th percentile were defined as PD-L1high and the remaining as PD-L1low.

Results

We identified 71 cases of EBVaGC and 193 EBV-negative ACRG samples as controls. EBVaGC showed higher expression of all queried immune genes compared to EBVnegACRG samples (p < 0.01). PD-L1 immunohistochemistry expression correlated with PD-L1 transcript expression (r = 0.63, p < 0.001). Tumor-infiltrating lymphocyte patterns were also found to be different between PD-L1low and PD-L1high groups. PD-L1low EBVaGC samples (n = 24, 34%) had consistently decreased expression of all other immune genes, such as CD8A, GZMA and PRF1 and PD-1 (p < 0.001). PD-L1low EBVaGC samples were also associated with worse disease-free survival (HR 5.03, p = 0.032) compared to PD-L1high EBVaGC samples.

Conclusions

A substantial proportion of EBVaGC does not express high levels of PD-L1 and other immune genes. EBVaGCs which have lower transcriptomic expression of PD-L1 tend to have a similarly low expression of other immune genes, IHC scores and a poorer prognosis.

Keywords

Epstein–Barr virus-associated gastric cancer Immune genes PD-L1 

Notes

Acknowledgements

RS is supported by a National Medical Research Council (NMRC) MOH Healthcare Research Scholarship, Singapore. PT is supported by Duke-NUS Medical School and the Biomedical Research Council, Agency for Science, Technology and Research. JL and KKM are supported by a Grant from the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI16C1990). This work was also supported by National Medical Research Council Grants TCR/009-NUHS/2013 and NMRC/STaR/0026/2015. This work was also provided by Korea National Research Foundation (NRF-2017R1D1A1B03032449).

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Ethical standards

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent to be included in the study, or the equivalent, was obtained from all patients.

Supplementary material

10120_2018_851_MOESM1_ESM.docx (15 kb)
Supplementary material 1 (DOCX 14 KB)
10120_2018_851_MOESM2_ESM.pdf (137 kb)
Supplementary Figure 1. KM survival curves of PD-L1high and PD-L1low samples after excluding samples older than 10 years (1996-2006) (PDF 136 KB)
10120_2018_851_MOESM3_ESM.pdf (120 kb)
Supplementary Figure 2. Scatter plot showing correlation between PD-L1 IHC CPS score (log-scale) and PD-L1 RNA transcript expression levels (log-scale) (PDF 120 KB)
10120_2018_851_MOESM4_ESM.docx (12 kb)
Supplementary material 4 (DOCX 12 KB)

References

  1. 1.
    The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014;513:202–9.CrossRefGoogle Scholar
  2. 2.
    Kim SY, Park C, Kim HJ, Park J, Hwang J, Kim JI, et al. Deregulation of immune response genes in patients with Epstein–Barr virus-associated gastric cancer and outcomes. Gastroenterology. 2015;148:137 e9–47 e9.Google Scholar
  3. 3.
    Naidoo J, Page DB, Wolchok JD. Immune modulation for cancer therapy. Br J Cancer. 2014;111:2214–9.CrossRefGoogle Scholar
  4. 4.
    Song HJ, Srivastava A, Lee J, Kim YS, Kim KM, Ki Kang W, et al. Host inflammatory response predicts survival of patients with Epstein–Barr virus-associated gastric carcinoma. Gastroenterology. 2010;139:84 e2–92 e2.CrossRefGoogle Scholar
  5. 5.
    Saito R, Abe H, Kunita A, Yamashita H, Seto Y, Fukayama M. Overexpression and gene amplification of PD-L1 in cancer cells and PD-L1(+) immune cells in Epstein–Barr virus-associated gastric cancer: the prognostic implications. Mod Pathol. 2017;30:427–39.CrossRefGoogle Scholar
  6. 6.
    Seo AN, Kang BW, Kwon OK, Park KB, Lee SS, Chung HY, et al. Intratumoural PD-L1 expression is associated with worse survival of patients with Epstein–Barr virus-associated gastric cancer. Br J Cancer. 2017;117:1753–60.CrossRefGoogle Scholar
  7. 7.
    Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21:449–56.CrossRefGoogle Scholar
  8. 8.
    Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015;160:48–61.CrossRefGoogle Scholar
  9. 9.
    Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390:2461–71.CrossRefGoogle Scholar
  10. 10.
    Muro K, Chung HC, Shankaran V, Geva R, Catenacci D, Gupta S, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol. 2016;17:717–26.CrossRefGoogle Scholar
  11. 11.
    Brody R, Zhang Y, Ballas M, Siddiqui MK, Gupta P, Barker C, et al. PD-L1 expression in advanced NSCLC: insights into risk stratification and treatment selection from a systematic literature review. Lung Cancer (Amsterdam, Netherlands). 2017;112:200–15.CrossRefGoogle Scholar
  12. 12.
    Lim JS, Sundar R, Chénard-Poirier M, Lopez J, Yap TA. Emerging biomarkers for PD-1 pathway cancer therapy. Biomark Med. 2017;11(1):53–67.CrossRefGoogle Scholar
  13. 13.
    Derks S, Liao X, Chiaravalli AM, Xu X, Camargo MC, Solcia E, et al. Abundant PD-L1 expression in Epstein–Barr Virus-infected gastric cancers. Oncotarget. 2016;7:32925–32.CrossRefGoogle Scholar
  14. 14.
    McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelekanou V, Rehman J, et al. Quantitative assessment of the heterogeneity of PD-L1 expression in non-small-cell lung cancer. JAMA Oncol. 2016;2:46–54.CrossRefGoogle Scholar
  15. 15.
    Cho J, Lee J, Bang H, Kim ST, Park SH, An JY, et al. Programmed cell death-ligand 1 expression predicts survival in patients with gastric carcinoma with microsatellite instability. Oncotarget. 2017;8:13320–8.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Park C, Cho J, Lee J, Kang SY, An JY, Choi MG, et al. Host immune response index in gastric cancer identified by comprehensive analyses of tumor immunity. Oncoimmunology. 2017;6:e1356150.CrossRefGoogle Scholar

Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2018

Authors and Affiliations

  • Raghav Sundar
    • 1
    • 2
  • Aditi Qamra
    • 2
  • Angie Lay Keng Tan
    • 2
  • Shenli Zhang
    • 2
  • Cedric Chuan Young Ng
    • 4
  • Bin Tean Teh
    • 4
  • Jeeyun Lee
    • 5
  • Kyoung-Mee Kim
    • 6
  • Patrick Tan
    • 2
    • 3
    • 7
    • 8
  1. 1.Department of Haematology-OncologyNational University Health SystemSingaporeSingapore
  2. 2.Cancer and Stem Cell Biology ProgramDuke-NUS Medical SchoolSingaporeSingapore
  3. 3.Biomedical Research CouncilAgency for Science, Technology and ResearchSingaporeSingapore
  4. 4.Laboratory of Cancer Epigenome, Department of Medical SciencesNational Cancer CentreSingaporeSingapore
  5. 5.Division of Hematology/Oncology, Department of Medicine, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulSouth Korea
  6. 6.Department of Pathology and Translational Genomics, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulSouth Korea
  7. 7.Cancer Science Institute of SingaporeNational University of SingaporeSingaporeSingapore
  8. 8.SingHealth/Duke-NUS Institute of Precision MedicineNational Heart Centre SingaporeSingaporeSingapore

Personalised recommendations