Aims: Developments in genomic pathology have led to novel molecular classification schemes in gastric cancers. Two of these new subtypes, Epstein-Barr virus (EBV)-associated and microsatellite instability-high (MSI-H), are associated with a dominant T-cell-mediated immune response. The roles of the immune modulators, indoleamine 2, 3-dioxygenase 1 (IDO1) and tryptophanyl-tRNA synthetase (WARS), have not been investigated in the context of this classification.
Methods and results: Using in situ hybridization and immunohistochemistry we subclassified 421 primary gastric adenocarcinomas into 5 subtypes, EBV-associated, epithelial to mesenchymal transition, MSI-H, p53-aberrant, and p53-wildtype tumors. Tumor-infiltrative lymphocytes were counted and protein expression of IDO1 and WARS was graded on tissue microarrays of these 421 tumors. High tumor-infiltrative lymphocytes as well as high expression of both IDO1 and WARS was found in EBV and MSI-H tumors. The prognostic effects of IDO1 and WARS expression were tumor subtype dependent. Although high expression levels of IDO1 and WARS were associated with poor prognosis in p53-aberrant, p53-wildtype, and all cancers combined, WARS expression was associated with better prognosis in MSI tumors.
Conclusions: The immunomodulators, IDO1 and WARs, are upregulated and have prognostic significance in EBV-associated and MSI-H tumors. Novel therapies targeting these proteins should be considered in the treatment of these patients.