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Distinct tumor immune microenvironments in primary and metastatic lesions in gastric cancer patients.

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.

SUBMITTER: Son SM

PROVIDER: S-EPMC7459099 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Distinct tumor immune microenvironments in primary and metastatic lesions in gastric cancer patients.

Son Seung-Myoung SM Woo Chang Gok CG Kim Dae Hoon DH Yun Hyo Yung HY Kim Hongsik H Kim Hee Kyung HK Yang Yaewon Y Kwon Jihyun J Kwon Minsuk M Kim Tae-Yong TY Kim Hyung-Don HD Koh June-Young JY Park Su-Hyung SH Shin Eui-Cheol EC Han Hye Sook HS

Scientific reports 20200831 1

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+ ce ...[more]

PMID: 32868848

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Project description:We performed RNA-seq to investigate the differences in the gene expression profiles between primary gastric cancer (PGC) and paired metastatic gastric cancer (MGC). RNA-sequencing was performed on 7 paired PGC and MGC FFPE tissues. The transcriptome profiling of the two groups (MGC vs PGC) including immune response gene signature was analyzed. Total RNA was isolated using Trizol reagent. Extracted RNA samples were processed using the QuantSeq 3’mRNA-Seq Library Prep Kit and sequenced on an Illumina NextSeq 500. QuantSeq 3’mRNA-Seq reads were aligned using Bowtie2. The alignment file was used to assemble transcripts and the Read Count data was processed based on quantile normalization method using EdgeR within R. We identified 519 differentially regulated genes between the two sets, 76 of which were significantly up-regulated and 443 significantly down-regulated in MGCs. Among DEGs, 33 immune response genes were selected using QuickGO database (https://www.ebi.ac.uk/QuickGO/), with majority (27/33) of them exhibiting downregulation in the MGC samples. In summary, RNA sequencing data revealed that immune-related gene expression were down-regulated in MGC compared to PGC. We performed RNA-seq to investigate the differences in the gene expression profiles between primary gastric cancer (PGC) and paired metastatic gastric cancer (MGC). RNA-sequencing was performed on 7 paired PGC and MGC FFPE tissues. The transcriptome profiling of the two groups (MGC vs PGC) including immune response gene signature was analyzed. Total RNA was isolated using Trizol reagent. Extracted RNA samples were processed using the QuantSeq 3’mRNA-Seq Library Prep Kit and sequenced on an Illumina NextSeq 500. QuantSeq 3’mRNA-Seq reads were aligned using Bowtie2. The alignment file was used to assemble transcripts and the Read Count data was processed based on quantile normalization method using EdgeR within R. We identified 519 differentially regulated genes between the two sets, 76 of which were significantly up-regulated and 443 significantly down-regulated in MGCs. Among DEGs, 33 immune response genes were selected using QuickGO database (https://www.ebi.ac.uk/QuickGO/), with majority (27/33) of them exhibiting downregulation in the MGC samples. In summary, RNA sequencing data revealed that immune-related gene expression were down-regulated in MGC compared to PGC.

Project description:BackgroundImmunotherapy has demonstrated a limited clinical efficacy in approximately 5% of cholangiocarcinoma. The main challenges for an effective immunotherapy response in cholangiocarcinoma arise from the tumor microenvironment, which is poorly understood.MethodsFor a comprehensive analysis of the tumor microenvironment in cholangiocarcinoma, we performed multiplex immunohistochemistry with two 15-marker immune panels and Nanostring assays for a comprehensive analysis of 104 surgically resected cholangiocarcinomas including intrahepatic, hilar, and distal cholangiocarcinoma. We also validated some key findings with a batch integration analysis of published single cell RNA sequencing data.ResultsThis study found that natural killer cells occupy the largest immune cell compartment in cholangiocarcinoma. Granzyme-B+CD8+ effector T cells are significantly associated with better overall survival in both intrahepatic and distal cholangiocarcinoma. Above 85% of intrahepatic cholangiocarcinomas with higher density of PD-1-EOMES-CD8+ effector T cells are associated with long-term survival. However, only the density of PD-1-EOMES-CD8+ T cells in the tumor areas, but not in the peripheries of the tumors, is prognostic. In all three cholangiocarcinoma subtypes, T regulator cells are significantly associated with a poor prognosis; however, M1 and M2 tumor-associated macrophages or PD-L1+ tumor-associated macrophage demonstrate different prognostic values. Combining PD-L1+ M1 or M2, PD-L1- M1 or M2 tumor-associated macrophages, and T regulator cells to subgroup intrahepatic and distal cholangiocarcinoma, the prognosis is significantly better distinguished. Moreover, PD-L1- M2 tumor-associated macrophages is associated with a good prognosis in intrahepatic and distal cholangiocarcinoma, suggesting this subtype of M2 tumor-associated macrophages may be antitumoral. Interestingly, lower densities of various types of immunosuppressive cells are associated with decreased infiltration of effector T cells in distal and hilar cholangiocarcinoma, but not in intrahepatic cholangiocarcinoma. In intrahepatic cholangiocarcinoma, PD-L1+ tumor-associated macrophages exert their immunosuppressive function likely through promoting T cell exhaustion.ConclusionsThis study suggests that the densities of Granzyme-B+CD8+ effector T cells and non-exhausted PD-1-EOMES-CD8+ T cells and the PD-L1 status in the tumor-associated macrophages are prognostic makers in cholangiocarcinomas. The study also supports targeting PD-L1+ tumor-associated macrophages as the immunotherapy for cholangiocarcinoma.

Dataset Information

Distinct tumor immune microenvironments in primary and metastatic lesions in gastric cancer patients.

Publications

Distinct tumor immune microenvironments in primary and metastatic lesions in gastric cancer patients.

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