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

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+/CD8High, 22.7%; PD-L1−/CD8Low, 22.7%; PD-L1+/CD8Low, 2.3%; PD-L1−/CD8High, 52.3%. PD-L1+/CD8High 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−/CD8High showed the best overall survival (OS) and PD-L1−/CD8Low the worst (P < 0.001). PD-L1 expression alone was not associated with OS, however, PD-L1−/CD8High type compared to PD-L1+/CD8High 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.

Prognostic stratification of patients with nasopharyngeal carcinoma based on tumor immune microenvironment

“…Significant correlations were observed between PD-L1 expression on tumor cells and CD3-positive (P 5 .001), CD4positive (P 5 .001), and CD8-positive (P 5 .025) TIL densities as well as between PD-L1 expression on immune cells and CD3-positive (P 5 .001), CD4-positive (P 5 .016), and CD8-positive (P 5 .002) TIL densities.3.6 | Classification of tumor immune microenvironmentWe classified the tumor immune microenvironment into 4 types based on the combination of PD-L1 expression tumor cells and CD8-positive TIL density (type I: tumor cells-PD-L1-positive/CD8 high ; type II: tumor cells-PD-L1-negative/ CD8 low ; type III: tumor cells-PD-L1-positive/CD8 low ; and type IV: tumor cells-PD-L1-negative/CD8 high ) as previously reported 21,22. Significant correlations were observed between PD-L1 expression on tumor cells and CD3-positive (P 5 .001), CD4positive (P 5 .001), and CD8-positive (P 5 .025) TIL densities as well as between PD-L1 expression on immune cells and CD3-positive (P 5 .001), CD4-positive (P 5 .016), and CD8-positive (P 5 .002) TIL densities.3.6 | Classification of tumor immune microenvironmentWe classified the tumor immune microenvironment into 4 types based on the combination of PD-L1 expression tumor cells and CD8-positive TIL density (type I: tumor cells-PD-L1-positive/CD8 high ; type II: tumor cells-PD-L1-negative/ CD8 low ; type III: tumor cells-PD-L1-positive/CD8 low ; and type IV: tumor cells-PD-L1-negative/CD8 high ) as previously reported 21,22.…”

“…15,[20][21][22] Because our multivariate analyses showed that tumor infiltration by CD8-positive T cells but not CD3-positive T cells was a prognostic factor, we used the CD8-positive TIL density for this classification. 15,[20][21][22] Because our multivariate analyses showed that tumor infiltration by CD8-positive T cells but not CD3-positive T cells was a prognostic factor, we used the CD8-positive TIL density for this classification.…”

Somatic mutational profiles of stage II and III gastric cancer according to tumor microenvironment immune type

“…TMIT III was the smallest subgroup among stage II and III GC cohorts, and a previous report of a pan‐cancer study using TCGA datasets also showed that TMIT III accounted for the smallest subtype except for a few specific entities such as glioblastoma, chromophobe type renal cell carcinoma, and pheochromocytoma . One reason for this could be the rarity of intrinsic oncogenic induction of PD‐L1, also suggesting that TMIT III might have unique genetic profile.…”

“…Practical application of TMIT classification in RNAseq data of 32 types of solid tumors has confirmed that TMIT I is associated with a higher mutational burden and oncogenic viral infection . In addition, in our previous study, we applied TMIT classification for human GC tissue samples and showed the close relationship between TMIT I and two distinct types of GCs—Epstein–Barr Virus + (EBV + ) and microsatellite instability high (MSI‐H) GCs—suggesting that a close association exists between TME and the molecular genetic characteristics of GCs . Considering these molecular genetic implications of the TMIT classification in GCs, it would be necessary to identify additional genetic characteristics that might show close association with the TMIT classification, such as the somatic mutation landscape of GCs.…”

Gastric cancer: Basic aspects

“…Koh et al 24 also addressed PD-L1 expression and CD8 + TILs in 392 stage II/III GCs from Korea. The majority of EBVaGC (92%) and MSI-H GC (67%) TILs were PD-L1 + /CD8 High , and analyzes of the TCGA and ACRG datasets validated that the EBVaGC and MSI-H CG in both were likely to be PD-L1 + /CD8 High .…”