Mismatch Repair Status of Gastric Cancer and Its Association with the Local and Systemic Immune Response

Shin, Su‐Jin; Kim, Sang Yong; Choi, Yoon Young; Son, Taeil; Cheong, Jae‐Ho; Hyung, Woo Jin; Noh, Sung Hoon; Park, Chung Gyu; Kim, Wook

doi:10.1634/theoncologist.2018-0273

Cited by 20 publications

(12 citation statements)

References 45 publications

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“…Our findings are in line with the frequency of EBV-positivity and microsatellite instability (MSI) in The Cancer Genome Atlas (TCGA) cohort (24). EBV-positive and dMMR or MSI-high gastric cancer has been associated with high intratumoral CD8 TIL density (26)(27)(28). In our study, we indeed found a significant correlation between EBV-positivity and intratumoral CD8 TILs.…”

Section: Discussionsupporting

confidence: 79%

Prognostic Biomarkers in Early-stage Gastric Adenocarcinoma Treated With Adjuvant Chemoradiotherapy

Pectasides

Chatzidakis

Kotoula

et al. 2020

Cancer Genomics Proteomics

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Background/Aim: Early-stage gastric cancer has a high risk of recurrence, despite trimodality therapy with surgery, chemotherapy and radiation. To improve patient selection for adjuvant chemoradiotherapy, we evaluated the prognostic significance of immunohistochemical and genetic biomarkers in patients with resected gastric adenocarcinoma. Patients and Methods: Tumors from 119 patients were subjected to immunohistochemistry for 12 protein biomarkers, as well as next-generation sequencing. Clinical and biomarker data were available for 91 patients. Results: EBV-positive tumors and tumors with mutations had higher intratumoral CD8 tumor-infiltrating lymphocyte density (p=0.009 and p=0.017, respectively). PIK3CA mutations were correlated with VEGFA overexpression (p=0.042), while KRAS mutations and HER2 expression were mutually exclusive (p=0.036). PTEN expression univariately confirmed longer overall survival (HR=0.27; p=0.046), while there was a trend between the presence of KRAS mutations and inferior disease-free and overall survival. Conclusion: PTEN protein expression and KRAS mutations may predict disease outcome in early-stage gastric cancer. These results need to be further validated in larger cohorts. Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related mortality worldwide (1). Patients with stage I disease treated with gastrectomy have a 5-year survival rate of approximately 65%, whereas patients with more advanced disease have poorer outcomes with a 5year survival rate of 30% (2, 3). Complete surgical resection is required to cure gastric cancer (4). However, given the high recurrence rate after surgery, additional therapeutic approaches have been explored. These therapeutic strategies include 277 This article is freely accessible online.

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Section: Discussionsupporting

confidence: 79%

Prognostic Biomarkers in Early-stage Gastric Adenocarcinoma Treated With Adjuvant Chemoradiotherapy

Pectasides

Chatzidakis

Kotoula

et al. 2020

Cancer Genomics Proteomics

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“…This study showed that the expression levels of immune checkpoint molecules were higher in the cluster.B group than in the cluster.A group, as expected. Numerous previous studies have shown that there is a signi cant correlation between tumor immunity and prognosis [18][19][20]. In this study, we found that the cluster.B group with elevated immune activity exhibited better survival.…”

Section: Discussionsupporting

confidence: 60%

Significance of Tumor Infiltrating Immune Cells (TIICs) in Endometrial carcinoma: A Bioinformatics Analysis

Hu¹,

Wang²,

Liu³

et al. 2021

Preprint

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Background: Increasing evidence has revealed that tumor-infiltrating immune cells (TIICs) are involved in the development of endometrial carcinoma (EC). In this study, we aimed to reveal the significance of 28 TIIC types in the classification and prognosis of EC. Methods: Single-sample gene set enrichment analysis (ssGSEA) was used to calculate the abundance of the 28 TIIC types in EC patients from TCGA database. A consensus clustering algorithm was used to group the EC patients. Principal component analysis (PCA) algorithms were performed to calculate an ICI score for each sample to predict the sensitivity to ICIs therapy based on the 28 TIIC types.Results: The EC patients from The Cancer Genome Atlas (TCGA) database were classified into two groups (cluster.A and cluster.B) based on the 28 types of TIIC using a consensus clustering algorithm. The patients in the cluster.B group had increased immune cell infiltration, and higher expression of human leucocyte antigen (HLA) genes, immune checkpoint molecules, and immune activation-related genes, suggesting that they may be more sensitive to immune checkpoint inhibitors (ICIs) therapy. Differential analysis between cluster.A and cluster.B identified 591 immune-related genes. We validated the immune regulation mechanism based on the 591 immune-related genes using another consensus clustering algorithm. The EC patients were divided into two groups (gene.cluster.A and gene.cluster.B) based on the 591 immune-related genes. The patients in the gene.cluster.B group had increased immune cell infiltration, and higher expression of HLA genes, immune checkpoint molecules, and immune activation-related genes. In addition, we also calculated an ICI score for each patient with EC to predict the sensitivity to ICIs therapy based on the 28 TIIC types using principal component analysis algorithms. Conclusions: In summary, the 28 types of TIIC play non-negligible roles in the development of EC. Our investigation of the 28 types of TIIC may help to guide ICIs treatment strategies for patients with EC.

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“…MSI is associated with higher density TILs, possibly in response to the new environment created by neoantigens 26 . Shin et al found that the density of each subgroup of TILs varied from the microsatellite status of GC, and CD8+ T cell density was highly increased in MSI-H GC 27 , 28 . MSI-H GC was significantly correlated with CD8+ T cells 29 .…”

Section: Discussionmentioning

confidence: 99%

“…The primary antibodies used in this study (including anti-MLH1, -PMS2, -MSH2, -MSH6, -CD8, and -CD68 antibodies), DAB chromogenic solution, and UltraSensitive TMSP detection kit were purchased from Maixin (Maixin Inc., Fujian, China). Anti-PDL1 antibody 28 - 8 (ab205921), anti-PD1 antibody [EPR4877(2)] (ab137132), and Universal HIER antigen retrieval reagent (10X) (ab208572) were purchased from Abcam (Cambridge, UK).…”

Section: Methodsmentioning

confidence: 99%

Expression of PD1/PDL1 in gastric cancer at different microsatellite status and its correlation with infiltrating immune cells in the tumor microenvironment

Wang¹,

Gong²,

Lv³

et al. 2021

J. Cancer

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Objective: The microsatellite status and tumor immune microenvironment have a remarkable influence on tumor immunotherapy. This study was performed to investigate programmed cell death protein 1/programmed death ligand 1 (PD1/PDL1) expression and their correlations with CD8+ T cell/CD68+ macrophage (CD68+ M) densities in gastric cancer (GC) at different microsatellite statuses. Methods: The expression of MLH1, PMS2, MSH2, and MSH6 was detected via immunohistochemistry (IHC) to determine the microsatellite status in 215 GC samples obtained from surgical resections. Furthermore, the expression of PD1, PDL1, CD8, and CD68 was detected in the samples via IHC, and the differences and correlations in GC at different microsatellite statuses were then analyzed. PDL1 expression in tumor cells was labeled as PDL1[T], while expression of PD1 and PDL1 in tumor-infiltrating immune cells was labeled as PD1 and PDL1, respectively. Kaplan-Meier analysis was used to evaluate the significance of PD1/PDL1 expression in determining overall survival. Multivariate Cox regression analysis was performed using SPSS software. P-values were determined using the log-rank test. Results: Our results indicated that PD1, PDL1[T], and PDL1 positivity rates were 59%, 35%, and 57% in 46 microsatellite unstable (MSI) GCs and 45%, 22%, and 40% in 169 microsatellite stable (MSS) GCs, respectively. Compared with MSS GC, PD1, PDL1[T], and PDL1 expression was higher in MSI GC (P = 0.109, 0.090, and 0.044, respectively). Additionally, CD8+ T cell and CD68+ M densities were higher in MSI GC than in MSS GC (P = 0.537 and <0.001, respectively). Additionally, CD8+ T cell/CD68+ M densities were evaluated according to tumor center and invasion front. We found that PD1 expression was significantly correlated with CD8+ T cell density at the invasion front of the MSI GC (P = 0.031), whereas PDL1 expression was significantly correlated to high CD68+ M density in the tumor center and invasion front of MSS GC (P = 0.001 and 0.014, respectively). Survival analysis showed that patients with PD1-positive and PDL1[T]/PDL1-negative GC had better prognosis (P = 0.012, 0.005, and 0.022, respectively). Multivariate Cox survival analysis showed that PDL1[T] was an independent prognostic factor for GC. Conclusion: The results suggested that PD1/PDL1 expression and immune response varied at different microsatellite statuses in GC. PD1/PDL1 expression was correlated with CD8+ T cell/CD68+ M densities in GC at different microsatellite statuses, especially at the invasion front. The patients exhibiting high PD1/PDL1 expression or high CD8+ T cell/CD68+ M densities MSI GC might be potential beneficiaries of PD1/PDL1 immunotherapy.

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Mismatch Repair Status of Gastric Cancer and Its Association with the Local and Systemic Immune Response

Cited by 20 publications

References 45 publications

Prognostic Biomarkers in Early-stage Gastric Adenocarcinoma Treated With Adjuvant Chemoradiotherapy

Prognostic Biomarkers in Early-stage Gastric Adenocarcinoma Treated With Adjuvant Chemoradiotherapy

Significance of Tumor Infiltrating Immune Cells (TIICs) in Endometrial carcinoma: A Bioinformatics Analysis

Expression of PD1/PDL1 in gastric cancer at different microsatellite status and its correlation with infiltrating immune cells in the tumor microenvironment

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