Prognostic perspectives of PD-L1 combined with tumor-infiltrating lymphocytes, Epstein-Barr virus, and microsatellite instability in gastric carcinomas

Abstract Background The prognostic potential of PD-L1 is currently unclear in gastric carcinomas, although the immune checkpoint PD-1/PD-L1 inhibitors have produced promising results in clinical trials. Methods We explored the prognostic implications of programmed death ligand 1 (PD-L1) in 514 conse...

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Main Authors: Euno Choi, Mee Soo Chang, Sun-ju Byeon, Heejin Jin, Kyeong Cheon Jung, Haeryoung Kim, Kook Lae Lee, Won Kim, Jin Hyun Park, Ki Hwan Kim, Jin-Soo Kim, In Sil Choi, Dong-Seok Han, Hye Seong Ahn, Seung Chul Heo
Format: Article
Language:English
Published: BMC 2020-06-01
Series:Diagnostic Pathology
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Online Access:http://link.springer.com/article/10.1186/s13000-020-00979-z
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author Euno Choi
Mee Soo Chang
Sun-ju Byeon
Heejin Jin
Kyeong Cheon Jung
Haeryoung Kim
Kook Lae Lee
Won Kim
Jin Hyun Park
Ki Hwan Kim
Jin-Soo Kim
In Sil Choi
Dong-Seok Han
Hye Seong Ahn
Seung Chul Heo
author_facet Euno Choi
Mee Soo Chang
Sun-ju Byeon
Heejin Jin
Kyeong Cheon Jung
Haeryoung Kim
Kook Lae Lee
Won Kim
Jin Hyun Park
Ki Hwan Kim
Jin-Soo Kim
In Sil Choi
Dong-Seok Han
Hye Seong Ahn
Seung Chul Heo
author_sort Euno Choi
collection DOAJ
description Abstract Background The prognostic potential of PD-L1 is currently unclear in gastric carcinomas, although the immune checkpoint PD-1/PD-L1 inhibitors have produced promising results in clinical trials. Methods We explored the prognostic implications of programmed death ligand 1 (PD-L1) in 514 consecutive surgically-resected gastric carcinomas. Overall survival and recurrence-free survival were evaluated. Immunohistochemistry for PD-L1, CD8, FOXP3, and PD-1, and molecular grouping by in situ hybridization for Epstein-Barr virus (EBV)-encoded small RNAs and multiplex PCR for microsatellite instability (MSI) markers were performed. Additionally, to explore the function inherent to PD-L1, PD-L1-specific siRNA transfection, cell proliferation, invasion, migration and apoptosis assays were conducted in five gastric carcinoma cell lines. Results PD-L1(+) tumor and immune cells were observed in 101 (20%) and 244 patients (47%), respectively. “Tumoral PD-L1(+)/immune cell PD-L1(-)/CD8+/low tumor-infiltrating lymphocytes (TILs),” and more advanced-stage tumors were associated with unfavorable clinical outcomes in the entire cohort through multivariate analysis. Furthermore, tumoral PD-L1(+)/FOXP3+/low TILs were associated with worse clinical outcomes in EBV-positive and MSI-high carcinomas. Tumoral PD-L1(+) alone was an adverse prognostic factor in EBV-positive carcinomas, but not in MSI-high carcinomas, whereas PD-L1(+) immune cells or FOXP3+/high TILs alone were correlated with a favorable prognosis. PD-L1 knockdown in gastric carcinoma cells suppressed cell proliferation, invasion and migration, and increased apoptosis, which were all statistically significant in two EBV(+) cell lines, but not all in three EBV(−) cell lines. Conclusions The prognostic impact of PD-L1 may depend on the tumor microenvironment, and statuses of EBV and MSI, although PD-L1 innately promotes cancer cell survival in cell-based assays. The combination of “tumoral PD-L1/immune cell PD-L1/CD8+ TILs” may serve as an independent prognostic factor. Tumoral PD-L1(+)/immune cell PD-L1(−)/CD8+/low TILs showing a worse prognosis may be beneficial for combinatorial therapies of anti-PD-L1/PD-1 and anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA4) that would promote effector T cells, thus attack the tumor.
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spelling doaj.art-c0c53c08269e4a599a2eaec4725130862022-12-21T19:18:45ZengBMCDiagnostic Pathology1746-15962020-06-0115111510.1186/s13000-020-00979-zPrognostic perspectives of PD-L1 combined with tumor-infiltrating lymphocytes, Epstein-Barr virus, and microsatellite instability in gastric carcinomasEuno Choi0Mee Soo Chang1Sun-ju Byeon2Heejin Jin3Kyeong Cheon Jung4Haeryoung Kim5Kook Lae Lee6Won Kim7Jin Hyun Park8Ki Hwan Kim9Jin-Soo Kim10In Sil Choi11Dong-Seok Han12Hye Seong Ahn13Seung Chul Heo14Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of MedicineDepartment of Pathology, Seoul National University Boramae Hospital, Seoul National University College of MedicineDepartment of Pathology, Seoul National University Boramae Hospital, Seoul National University College of MedicineMedical Research Collaborating Center, Department of Biostatistics, Seoul National University Boramae HospitalDepartment of Pathology, Seoul National University Hospital, Seoul National University College of MedicineDepartment of Pathology, Seoul National University Hospital, Seoul National University College of MedicineDepartment of Internal Medicine, Seoul National University Boramae Hospital, Seoul National University College of MedicineDepartment of Internal Medicine, Seoul National University Boramae Hospital, Seoul National University College of MedicineDepartment of Internal Medicine, Seoul National University Boramae Hospital, Seoul National University College of MedicineDepartment of Internal Medicine, Seoul National University Boramae Hospital, Seoul National University College of MedicineDepartment of Internal Medicine, Seoul National University Boramae Hospital, Seoul National University College of MedicineDepartment of Internal Medicine, Seoul National University Boramae Hospital, Seoul National University College of MedicineDepartment of Surgery, Seoul National University Boramae Hospital, Seoul National University College of MedicineDepartment of Surgery, Seoul National University Boramae Hospital, Seoul National University College of MedicineDepartment of Surgery, Seoul National University Boramae Hospital, Seoul National University College of MedicineAbstract Background The prognostic potential of PD-L1 is currently unclear in gastric carcinomas, although the immune checkpoint PD-1/PD-L1 inhibitors have produced promising results in clinical trials. Methods We explored the prognostic implications of programmed death ligand 1 (PD-L1) in 514 consecutive surgically-resected gastric carcinomas. Overall survival and recurrence-free survival were evaluated. Immunohistochemistry for PD-L1, CD8, FOXP3, and PD-1, and molecular grouping by in situ hybridization for Epstein-Barr virus (EBV)-encoded small RNAs and multiplex PCR for microsatellite instability (MSI) markers were performed. Additionally, to explore the function inherent to PD-L1, PD-L1-specific siRNA transfection, cell proliferation, invasion, migration and apoptosis assays were conducted in five gastric carcinoma cell lines. Results PD-L1(+) tumor and immune cells were observed in 101 (20%) and 244 patients (47%), respectively. “Tumoral PD-L1(+)/immune cell PD-L1(-)/CD8+/low tumor-infiltrating lymphocytes (TILs),” and more advanced-stage tumors were associated with unfavorable clinical outcomes in the entire cohort through multivariate analysis. Furthermore, tumoral PD-L1(+)/FOXP3+/low TILs were associated with worse clinical outcomes in EBV-positive and MSI-high carcinomas. Tumoral PD-L1(+) alone was an adverse prognostic factor in EBV-positive carcinomas, but not in MSI-high carcinomas, whereas PD-L1(+) immune cells or FOXP3+/high TILs alone were correlated with a favorable prognosis. PD-L1 knockdown in gastric carcinoma cells suppressed cell proliferation, invasion and migration, and increased apoptosis, which were all statistically significant in two EBV(+) cell lines, but not all in three EBV(−) cell lines. Conclusions The prognostic impact of PD-L1 may depend on the tumor microenvironment, and statuses of EBV and MSI, although PD-L1 innately promotes cancer cell survival in cell-based assays. The combination of “tumoral PD-L1/immune cell PD-L1/CD8+ TILs” may serve as an independent prognostic factor. Tumoral PD-L1(+)/immune cell PD-L1(−)/CD8+/low TILs showing a worse prognosis may be beneficial for combinatorial therapies of anti-PD-L1/PD-1 and anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA4) that would promote effector T cells, thus attack the tumor.http://link.springer.com/article/10.1186/s13000-020-00979-zStomach cancerPD-L1Tumor-infiltrating lymphocytesEpstein-Barr virusMicrosatellite instabilityPrognosis
spellingShingle Euno Choi
Mee Soo Chang
Sun-ju Byeon
Heejin Jin
Kyeong Cheon Jung
Haeryoung Kim
Kook Lae Lee
Won Kim
Jin Hyun Park
Ki Hwan Kim
Jin-Soo Kim
In Sil Choi
Dong-Seok Han
Hye Seong Ahn
Seung Chul Heo
Prognostic perspectives of PD-L1 combined with tumor-infiltrating lymphocytes, Epstein-Barr virus, and microsatellite instability in gastric carcinomas
Diagnostic Pathology
Stomach cancer
PD-L1
Tumor-infiltrating lymphocytes
Epstein-Barr virus
Microsatellite instability
Prognosis
title Prognostic perspectives of PD-L1 combined with tumor-infiltrating lymphocytes, Epstein-Barr virus, and microsatellite instability in gastric carcinomas
title_full Prognostic perspectives of PD-L1 combined with tumor-infiltrating lymphocytes, Epstein-Barr virus, and microsatellite instability in gastric carcinomas
title_fullStr Prognostic perspectives of PD-L1 combined with tumor-infiltrating lymphocytes, Epstein-Barr virus, and microsatellite instability in gastric carcinomas
title_full_unstemmed Prognostic perspectives of PD-L1 combined with tumor-infiltrating lymphocytes, Epstein-Barr virus, and microsatellite instability in gastric carcinomas
title_short Prognostic perspectives of PD-L1 combined with tumor-infiltrating lymphocytes, Epstein-Barr virus, and microsatellite instability in gastric carcinomas
title_sort prognostic perspectives of pd l1 combined with tumor infiltrating lymphocytes epstein barr virus and microsatellite instability in gastric carcinomas
topic Stomach cancer
PD-L1
Tumor-infiltrating lymphocytes
Epstein-Barr virus
Microsatellite instability
Prognosis
url http://link.springer.com/article/10.1186/s13000-020-00979-z
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