Host immune response index in gastric cancer identified by comprehensive analyses of tumor immunity

Abstract

Tumor infiltrating lymphocytes (TIL) in Epstein-Barr virus (EBV)-associated/microsatellite-unstable (MSI) gastric carcinomas (GC) constitute immune-active principal cellular components of tumor microenvironment and contribute to better prognosis. With the remarkable success of cancer immunotherapies, there is an urgent need for a comprehensive understanding of tumor-immune interactions in patients with GC in the context of host immune response. To identify GC subtype-specific immune response gene set, we tested differentially expressed genes for MSI and EBV+ GC subtypes in randomly selected test set (n = 278) in merged ACRG-SMC microarray and TCGA RNA sequencing data set. We identified Host ImmunE Response index (HIERÏ) consisting of 29 immune genes classifying GC patients into robust 3 groups with prognostic significance. Immune-high cluster 1 was enriched with PD-L1/EBV+/MSI/TIL with the best clinical outcome while immune-low cluster 3 displayed worst outcome and exemplified with PD-L1/EBV-/MSS. The results were validated in the same cohort (n = 279) and independent cohort (n = 181) with RNA from formalin-fixed paraffin-embedded (FFPE) tissue. Unexpectedly, nearly half of GC in cluster 1 were EBV-/MSS and 10% of cluster 3 GC were EBV+/MSI GC patients, suggesting that in addition to EBV+/MSI GC subtypes, EBV-/MSS subtype also constitutes almost half of high immune cluster and would be a good candidate for immune checkpoint inhibitor therapy. In contrary, almost 10% of EBV+/MSI GC patients may not respond to immune checkpoint inhibitor therapy. Thus, our HIERÏ gene signature demonstrates the potential to subclassify tumor immunity levels, predict prognosis and help immunotherapeutic decisions.

Functional loss of ARID1A is tightly associated with high PD‐L1 expression in gastric cancer

“…Recent studies have conversely indicated that PD-L1 is a favor prognostic factor in GCs. 19,28,29 In support of these recent studies, our data additionally demonstrated that tumor PD-L1 positivity was associated with better survival for patients with various molecular subtypes of GCs, although most of these were not statistically significant. However, considering that loss of ARID1A is correlated with PD-L1 positivity and that loss of ARID1A has a negative prognostic role, this contradictory result is not easily understood.…”

“…However, these previous studies used various (or sometimes unvalidated) antibodies and some interpreted cytoplasmic/nuclear staining as positive, the reliability of their results might be low. Recent studies have conversely indicated that PD‐L1 is a favor prognostic factor in GCs . In support of these recent studies, our data additionally demonstrated that tumor PD‐L1 positivity was associated with better survival for patients with various molecular subtypes of GCs, although most of these were not statistically significant.…”

“…As ARID1A‐deficient tumors do not always express PD‐L1, we may hypothesize that some ARID1A‐deficient tumors expressing PD‐L1 recruit increased tumor infiltrating lymphocytes (TILs), and such increase of T cells may somehow manage to limit tumor growth and progression induced by loss of ARID1A. In line with this, previous studies exhibited that PD‐L1 expression was associated with increased TILs . However, even if this is true, the role of tumor PD‐L1 expression and the relationship between tumor PD‐L1 and TILs are still obscure, which need to be investigated in the future.…”

“…In line with this, previous studies exhibited that PD-L1 expression was associated with increased TILs. 29,30 However, even if this is true, the role of tumor PD-L1 expression and the relationship between tumor PD-L1 and TILs are still obscure, which need to be investigated in the future.…”

Geographic variation in molecular subtype for gastric adenocarcinoma

“…The clinical significance has been evaluated in a recent study using the TCGA proposed comprehensive molecular classification of patients with GC into four subtypes: Epstein-Barr virus (EBV), chromosomal instability (CIN), MSI and genomically stable (GS). Sohn et al reported that CIN and MSI subtypes had better overall survival than GS, but worse than EBV subtypes 4. Identification of molecular subtypes of GC may offer improved ways to monitor the progression, and predict prognosis5 and distinct therapeutic features 6.…”