Better prognosis of gastric cancer patients with high levels of tumor infiltrating lymphocytes is counteracted by PD-1 expression

Abstract

The prognostic potential of anti-tumor immune responses is becoming increasingly important in adenocarcinoma of the gastroesophageal junction and stomach (AGE/S) especially regarding the use of immune checkpoint inhibitors. This study analyzes for the first time the prognostic impact of tumor-infiltrating lymphocytes (TILs) and checkpoint inhibitors in a large Caucasian cohort in patients with AGE/S. We screened tissue samples from 438 therapy-naïve patients with AGE/S undergoing surgery between 1992 and 2005, examined in a tissue microarray (TMA) and stained against human CD3, CD4, CD8, PD-1, and PD-L1. Out of 438 tissue samples, 210 were eligible for multivariate analysis. This revealed that high infiltration with CD3 + , CD4 + , or CD8 + TILs was associated with an increased overall survival in AGE/S patients, which could only be confirmed in multivariate analysis for CD3 (HR: 0.326; p = .023). Independent improved survival was limited to gastric cancer patients and to early tumor stages as long as TILs did not express PD-1 (HR: 1.522; p = .021). Subgroup analyses indicate that TIL-dependent anti-tumor immune response is only effective in gastric cancer patients in early stages of disease in PD-1 negative TILs. Combined analysis of PD-1 and CD3 could serve as a prognostic marker for the clinical outcome of gastric cancer patients and could also be of interest for immunotherapy.

Prognostic impact of activin subunit inhibin beta A in gastric and esophageal adenocarcinomas

“…We previously reported on longer survival of patients with AEG/ASs exhibiting high CD4 + cell infiltration [ 29 ]. Even though a non-statistical significant trend towards correlation between activin protein expression and overall survival was seen in tumors exhibiting a low CD4 + T-cell infiltration (high 57.4 +/− 11.0 months versus low 47.1 +/− 5.7 months, p = n.s.…”

“…Immunohistochemical analysis of expression of CD3 + , CD4 + and CD8 + , as well as PD-1 and PD-L1 was performed on consecutive TMA sections using a specific monoclonal antibody as previously described. Correlation of prognosis with these factors in this cohort as well as representative images of the stainings were previously published [ 29 ].…”

Tumor budding in gastric adenocarcinoma; reflections on tumor microenvironment and programmed death ligand 1 (PD-L1) expression

“…The suppression of anti-tumor T cell responses is further magnified by increased PD-L1 expression on tumor cells, thereby upregulating tumor progression. This also could explain why good prognosis of gastric cancer cases with high TILs levels as reported by some studies is countered by expression of PD-1 expression (24).…”

“…However, the effect of PD-L1 on overall survival is still controversial. Some studies reported PD-L1 as a poor prognostic factor (18,24), whereas, others either found it was a good indicator (20) or it had a non-significant relationship with overall survival (17).…”

The clinical prognostic value of PD-L1 after concurrent chemoradiotherapy in Chinese nasopharyngeal carcinoma patients

“…ICI treatments benefit some patients with metastatic cancers, but predictive biomarkers are urgently needed. PD-L1 has been shown to be overexpressed in numerous cancer cell types and is associated with different clinical outcomes, either better or worse, depending on the tumor category (12)(13)(14)(15). PD-L1 is one of the immune-checkpoint molecules that regulates Type 1 T helper (Th1) immune responses and mediates cancer immune evasion.…”