Abstract
Purpose
Immunoscore can effectively predict prognosis in patients with colon cancer; however, its clinical application is limited. We modified the Immunoscore and created a tumor immune microenvironment (TIM) classification system for gastric carcinoma. Unlike previous studies that used small sample sizes or focused on particular immune-cell subtypes, our simplified system enables pathologists to classify gastric carcinomas intuitively using H&E-stained sections.
Methods
Samples from 326 patients with advanced gastric carcinoma were reviewed and analyzed by pathologists using simple determination and digital image analysis. Comprehensive results of cancer-panel sequencing, Epstein-Barr‒virus (EBV) status, and PD-L1, HER2, ATM, PTEN, MET, FGFR2, and EGFR immunohistochemistry were evaluated with respect to the TIM class.
Results
The TIM was classified as “hot” (n = 22), “immunosuppressed” (n = 178), “excluded” (n = 83), or “cold” (n = 43). TIM category was significantly associated with numbers of frameshift mutations (P < 0.001) and high tumor mutational burden (P < 0.004), and predicted overall survival. It was also significantly associated with age, histological type, degree of fibrosis, PD-L1 expression, loss of ATM and PTEN expression (P < 0.001), sex, EBV positivity, and HER2 overexpression (P < 0.04). “Hot” tumors were frequent in PD-L1 expressing and EBV-positive samples, and in those with ATM and PTEN loss. “Excluded” tumors were frequent in HER2-positive cases, whereas “cold” tumors were more frequent in younger patients with poorly cohesive histology and high fibrosis levels.
Conclusions
TIM classification system for gastric carcinoma has prognostic significance and results in classes that are associated with molecular characteristics.
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Availability of data and material
Data and material are available upon request.
Code availability
Not applicable.
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Funding
This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, Republic of Korea and ICT (grant numbers NRF-2017R1E1A1A01075005 and NRF-2017R1A2B4012436) and a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number HR20C0025).
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Hyunjin Kim, You Jeong Heo, Soomin Ahn, and Kyoung-Mee Kim designed the study. Hyunjin Kim, You Jeong Heo, Yoon Ah Cho, So Young Kang, and Soomin Ahn conducted the data analysis. Hyunjin Kim, You Jeong Heo, and Kyoung-Mee Kim wrote the paper. Soomin Ahn and Kyoung-Mee Kim revised the paper. All authors read and approved the final manuscript.
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Online Resource Fig. S1 Heatmap showing associations between gene mutations and TIM classification. Online Resource Fig. S2 Kaplan-Meier curve depicting overall survival in Stage II and III tumors. (a) is according to the four TIM classes, and (b) is according to three TIM classes, where “excluded” and “immunosuppressed” are merged into “intermediate” (PDF 284 KB)
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Kim, H., Heo, Y.J., Cho, Y.A. et al. Tumor immune microenvironment is influenced by frameshift mutations and tumor mutational burden in gastric cancer. Clin Transl Oncol 24, 556–567 (2022). https://doi.org/10.1007/s12094-021-02714-6
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DOI: https://doi.org/10.1007/s12094-021-02714-6