Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas

Abstract

ObjectiveDifferences in gastric cancer (GC) clinical outcomes between patients in Asian and non-Asian countries has been historically attributed to variability in clinical management. However, recent international Phase III trials suggest that even with standardised treatments, GC outcomes differ by geography. Here, we investigated gene expression differences between Asian and non-Asian GCs, and if these molecular differences might influence clinical outcome.DesignWe compared gene expression profiles of 1016 GCs from six Asian and three non-Asian GC cohorts, using a two-stage meta-analysis design and a novel biostatistical method (RUV-4) to adjust for technical variation between cohorts. We further validated our findings by computerised immunohistochemical analysis on two independent tissue microarray (TMA) cohorts from Asian and non-Asian localities (n=665).ResultsGene signatures differentially expressed between Asians and non-Asian GCs were related to immune function and inflammation. Non-Asian GCs were significantly enriched in signatures related to T-cell biology, including CTLA-4 signalling. Similarly, in the TMA cohorts, non-Asian GCs showed significantly higher expression of T-cell markers (CD3, CD45R0, CD8) and lower expression of the immunosuppressive T-regulatory cell marker FOXP3 compared to Asian GCs (p<0.05). Inflammatory cell markers CD66b and CD68 also exhibited significant cohort differences (p<0.05). Exploratory analyses revealed a significant relationship between tumour immunity factors, geographic locality-specific prognosis, and postchemotherapy outcomes.ConclusionsAnalyses of >1600 GCs suggest that Asian and non-Asian GCs exhibit distinct tumour immunity signatures related to T-cell function. These differences may influence geographical differences in clinical outcome, and the design of future trials particularly in immuno-oncology.

Immune checkpoints programmed death 1 ligand 1 and cytotoxic T lymphocyte associated molecule 4 in gastric adenocarcinoma

“…22,23 Furthermore, gastric adenocarcinoma in Asian patients is genetically and probably immunologically distinct from Causasian patients. 34 Although these trials showed conflicting results regarding the prognostic impact, all studies described similar frequencies of PD-L1 expression. 22,23 Additionally, we found an increased expression of PD-L1 on metastatic tumor cells further underlining its role in the natural biology of gastric adenocarcinoma.…”

Lymphadenectomy: state of the art

“…In particular, some studies reported that with the implementation of lymphadenectomy procedures with time, a progressive reduction of locoregional recurrences has been observed (26). However, it should be emphasized that when comparing long-term results from Eastern and Western series, a significant better outcome at the same stage is observed in the former, suggesting potential biological differences related to the tumor, to the ethnicity or to the immunological system (50)(51)(52)(53)(54). When analysing long-term results in Western large series, it is evident that survival rates at advanced pT (serosal involvement) and pN stages (N3a and N3b) are unsatisfactory, even when submitting patients to extended lymphadenectomy (55).…”

Immune Checkpoint Inhibition in Gastro-Oesophageal Cancer

“…This is relevant because patients with gastrooesophageal cancer in Asia have, stage for stage, better survival than patients from non-Asian countries and may have a different immune-infiltrate compared with non-Asian patients [16]. Nivolumab has also been evaluated in non-Asian patients in the CheckMate-032 trial which was a non-randomized Phase I/II cohort-study of nivolumab monotherapy and combination nivolumab + ipilimumab (anti-CTLA4) in non-Asian, PD-L1-unselected gastro-oesophageal cancer patients.…”