Clinicopathologic implications of immune classification by PD-L1 expression and CD8-positive tumor-infiltrating lymphocytes in stage II and III gastric cancer patients

// Jiwon Koh 1 , Chan-Young Ock 2 , Jin Won Kim 3 , Soo Kyung Nam 4 , Yoonjin Kwak 4 , Sumi Yun 5 , Sang-Hoon Ahn 6 , Do Joong Park 6 , Hyung-Ho Kim 6 , Woo Ho Kim 1 , Hye Seung Lee 4 1 Department of Pathology, Seoul National University College of Medicine, Jongno-gu, Seoul 03080, Republic of Korea 2 Department of Internal Medicine, Seoul National University Hospital, Jongno-gu, Seoul 03080, Republic of Korea 3 Department of Internal Medicine, Seoul National University Bundang Hospital, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Republic of Korea 4 Department of Pathology, Seoul National University Bundang Hospital, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Republic of Korea 5 Department of Pathology, Soonchunhyang University Seoul Hospital, Yongsan-gu, Seoul 04401, Republic of Korea 6 Department of Surgery, Seoul National University Bundang Hospital, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Republic of Korea Correspondence to: Hye Seung Lee, email: hye2@snu.ac.kr Keywords: gastric cancer, programmed cell death 1 ligand 1, tumor-infiltrating lymphocytes, cancer microenvironment Received: November 22, 2016 Accepted: February 06, 2017 Published: February 17, 2017 ABSTRACT We co-assessed PD-L1 expression and CD8 + tumor-infiltrating lymphocytes in gastric cancer (GC), and categorized into 4 microenvironment immune types. Immunohistochemistry ( PD-L1 , CD8, Foxp3, E-cadherin, and p53), PD-L1 mRNA in situ hybridization (ISH), microsatellite instability (MSI), and EBV ISH were performed in 392 stage II/III GCs treated with curative surgery and fluoropyrimidine-based adjuvant chemotherapy, and two public genome databases were analyzed for validation. PD-L1 + was found in 98/392 GCs (25.0%). The proportions of immune types are as follows: PD-L1 + /CD8 High, 22.7%; PD-L1 − /CD8 Low , 22.7%; PD-L1 + /CD8 Low , 2.3%; PD-L1 − /CD8 High , 52.3%. PD-L1 + /CD8 High type accounted for majority of EBV + and MSI-high (MSI-H) GCs (92.0% and 66.7%, respectively), and genome analysis from public datasets demonstrated similar pattern. PD-L1 − /CD8 High showed the best overall survival (OS) and PD-L1 − /CD8 Low the worst ( P < 0.001). PD-L1 expression alone was not associated with OS, however, PD-L1 − /CD8 High type compared to PD-L1 + /CD8 High was independent favorable prognostic factor of OS by multivariate analysis ( P = 0.042). Adaptation of recent molecular classification based on EBV, MSI, E-cadherin, and p53 showed no significant survival differences. These findings support the close relationship between PD-L1/CD8 status based immune types and EBV + , MSI-H GCs, and their prognostic significance in stage II/III GCs.