Abstract

This study compared the tumor immune microenvironments (TIMEs) of primary gastric cancer (PGC) and paired metastatic gastric cancer (MGC). CD4+ and CD8+ T-cell density and PD-L1 expression were evaluated by multiplex immunohistochemistry, DNA mismatch repair (MMR) by immunohistochemistry, and immune-related genes by RNA sequencing. Twenty-three patients who underwent surgical treatment for PGC and MGC were enrolled in this study. CD8+ T-cell, PD-L1+ cell, and PD-L1+CK+ cell densities were significantly lower in MGC than PGC. PD-L1 positivity using a combined positive score (≥ 1%) and deficient MMR were observed in 52.2% and 8.7% of PGC samples, respectively, whereas both occurred in only 4.3% of MGC samples. The most frequent TIME types were inflamed (34.8%) and adaptive immune resistance (34.8%) in PGC, and immune desert (65.2%) and immunological ignorance (73.9%) in MGC. In transcriptome analysis, the expression of the T-cell inflamed gene set and co-stimulatory gene module was down-regulated in MGC compared to PGC. The total CD8+ T-cell density was an independent prognostic marker in both PGC and MGC (univariate P = 0.002, multivariate P = 0.006). Our result suggest that the TIME of metastatic tumors was less immunologically active compared to that of primary tumors in gastric cancer patients.

Highlights

  • This study compared the tumor immune microenvironments (TIMEs) of primary gastric cancer (PGC) and paired metastatic gastric cancer (MGC). ­CD4+ and ­CD8+ T-cell density and programmed death-ligand 1 (PD-L1) expression were evaluated by multiplex immunohistochemistry, DNA mismatch repair (MMR) by immunohistochemistry, and immune-related genes by RNA sequencing

  • The assessment of immune-related biomarkers for MGC was based on the tumor immune microenvironment (TIME) of primary gastric cancer (PGC) specimens obtained during curative resected gastrectomy before recurrence, or PGC specimens acquired at the time of initial diagnosis before palliative systemic therapy

  • In gastric cancer patients, immune-related biomarkers, such as T-cell density, Deficient MMR (dMMR) status, PD-L1 expression, and the T-cell activation-related gene signature, were significantly lower in metastatic tumors than in primary tumors

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Summary

Introduction

This study compared the tumor immune microenvironments (TIMEs) of primary gastric cancer (PGC) and paired metastatic gastric cancer (MGC). ­CD4+ and ­CD8+ T-cell density and PD-L1 expression were evaluated by multiplex immunohistochemistry, DNA mismatch repair (MMR) by immunohistochemistry, and immune-related genes by RNA sequencing. This study compared the tumor immune microenvironments (TIMEs) of primary gastric cancer (PGC) and paired metastatic gastric cancer (MGC). Palliative systemic therapy is a primary treatment option in patients with metastatic gastric cancer (MGC) to alleviate disease-related symptoms and improve ­survival[1,2]. The assessment of immune-related biomarkers for MGC was based on the tumor immune microenvironment (TIME) of primary gastric cancer (PGC) specimens obtained during curative resected gastrectomy before recurrence, or PGC specimens acquired at the time of initial diagnosis before palliative systemic therapy. We compared the TIMEs of primary and paired metastatic gastric cancer, including T-cell density, PD-L1 expression, MMR status, EBV positivity, and immune-related gene expression. We evaluated the prognostic impact of tumor-infiltrating T cells in primary and metastatic tumors in gastric cancer patients

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