Shaolei Lu1, Li Juan Wang1, Kara Lombardo2, Yoonjin Kwak3, Woo Ho Kim4, Murray B Resnick1. 1. Department of Pathology and Laboratory Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI. 2. Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD. 3. Department of Pathology, Seoul National University Hospital. 4. Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
Abstract
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.
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.
Authors: Mikhail Binnewies; Edward W Roberts; Kelly Kersten; Vincent Chan; Douglas F Fearon; Miriam Merad; Lisa M Coussens; Dmitry I Gabrilovich; Suzanne Ostrand-Rosenberg; Catherine C Hedrick; Robert H Vonderheide; Mikael J Pittet; Rakesh K Jain; Weiping Zou; T Kevin Howcroft; Elisa C Woodhouse; Robert A Weinberg; Matthew F Krummel Journal: Nat Med Date: 2018-04-23 Impact factor: 53.440
Authors: Kenneth Friedman; Alexander S Brodsky; Shaolei Lu; Stephanie Wood; Anthony J Gill; Kara Lombardo; Dongfang Yang; Murray B Resnick Journal: Mod Pathol Date: 2016-03-11 Impact factor: 7.842
Authors: Ana Bermúdez; Isabel Arranz-Salas; Silvia Mercado; Juan A López-Villodres; Virginia González; Francisca Ríus; María V Ortega; Carmen Alba; Isabel Hierro; Diego Bermúdez Journal: Diagnostics (Basel) Date: 2021-05-25