Raghav Sundar1,2, Aditi Qamra2, Angie Lay Keng Tan2, Shenli Zhang2, Cedric Chuan Young Ng3, Bin Tean Teh3, Jeeyun Lee4, Kyoung-Mee Kim5, Patrick Tan6,7,8,9. 1. Department of Haematology-Oncology, National University Health System, Singapore, Singapore. 2. Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore. 3. Laboratory of Cancer Epigenome, Department of Medical Sciences, National Cancer Centre, Singapore, Singapore. 4. Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 5. Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. kkmkys@skku.edu. 6. Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore. gmstanp@duke-nus.edu.sg. 7. Biomedical Research Council, Agency for Science, Technology and Research, Singapore, Singapore. gmstanp@duke-nus.edu.sg. 8. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. gmstanp@duke-nus.edu.sg. 9. SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore, Singapore. gmstanp@duke-nus.edu.sg.
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.
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 cancerpatients 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.
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