Prognostic Significance of PD-1, PD-L1 and CD8 Gene Expression Levels in Gastric Cancer

Ito, Shuhei; Masuda, Takaaki; Noda, Manjiro; Hu, Qingjiang; Shimizu, Dai; Kuroda, Yasuhiro; Eguchi, Hidetoshi; Tobo, Taro; Utsunomiya, Tohru; Mimori, Koshi

doi:10.1159/000506075

Cited by 15 publications

(13 citation statements)

References 30 publications

(44 reference statements)

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“…In particularly, patients with higher PRIs have higher expression levels of ICI genes (TIM-3, PD-L1 and CTLA-4). However, it is still controversial that PD-L1 expression is a favorable or adverse prognostic factor in GC according to previous researches (72)(73)(74)(75)(76)(77). As illustrated before, TGF-b, IL-6, IL-10 and TIM3 could directly or indirectly promote EMT or peritoneal metastasis which was in line with our findings (78, 79), and it is reasonable to speculate that antibodies targeting these molecules may be a preferable choice for PR high risk subgroup.…”

Section: Discussionsupporting

confidence: 89%

Immune Landscape of Gastric Carcinoma Tumor Microenvironment Identifies a Peritoneal Relapse Relevant Immune Signature

Zhang

et al. 2021

Front. Immunol.

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BackgroundGastric cancer (GC) still represents the third leading cause of cancer-related death worldwide. Peritoneal relapse (PR) is the most frequent metastasis occurring among patients with advanced gastric cancer. Increasingly more evidence have clarified the tumor immune microenvironment (TIME) may predict survival and have clinical significance in GC. However, tumor-transcriptomics based immune signatures derived from immune profiling have not been established for predicting the peritoneal recurrence of the advanced GC.MethodsIn this study, we depict the immune landscape of GC by using transcriptome profiling and clinical characteristics retrieved from GSE62254 of Gene Expression Omnibus (GEO). Immune cell infiltration score was evaluated via single-sample gene set enrichment (ssGSEA) analysis algorithm. The least absolute shrinkage and selection operator (LASSO) Cox regression algorithm was used to select the valuable immune cells and construct the final model for the prediction of PR. The receiver operating characteristic (ROC) curve and the Kaplan-Meier curve were used to check the accuracy of PRIs. Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to explore the molecular pathways associated with PRIs.ResultsA peritoneal recurrence related immune score (PRIs) with 10 immune cells was constructed. Compared to the low-PRIs group, the high-PRIs group had a greater risk. The upregulation of the focal adhesion signaling was observed in the high-PRIs subtype by GSEA and KEGG. Multivariate analysis found that both in the internal training cohort and the internal validation cohort, PRIs was a stable and independent predictor for PR. A nomogram that integrated clinicopathological features and PRIs to predict peritoneal relapse was constructed. Subgroup analysis indicated that the PRIs could obviously distinguish peritoneal recurrence in different molecular subtypes, pathological stages and Lauren subtypes, in which PRIs of Epithelial-Mesenchymal Transitions (EMT) subtype, III-IV stage and diffuse subtype are higher respectively.ConclusionOverall, we performed a comprehensive evaluation of the immune landscape of GC and constructed a predictive PR model based on the immune cell infiltration. The PRIs represents novel promising feature of predicting peritoneal recurrence of GC and sheds light on the improvement of the personalized management of GC patients after surgery.

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Section: Discussionsupporting

confidence: 89%

Immune Landscape of Gastric Carcinoma Tumor Microenvironment Identifies a Peritoneal Relapse Relevant Immune Signature

Zhang

et al. 2021

Front. Immunol.

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“…A meta-analysis showed that PDL1 negativity was associated with better overall survival in GC 24 . Low PD1, PDL1, and CD8 mRNA levels were more significantly associated with a poor prognosis 40 . A study revealed that CD68+ TAMs had no significant effect on OS 41 .…”

Section: Discussionmentioning

confidence: 92%

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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“…PDL1 overexpression has been associated to higher number of lymph node metastasis, larger tumor size, increased depth of invasion and poorer overall survival in various cancers [ 58 , 61 ]. According to a previous study, PD1, PDL1 and CD8 mRNA levels were significantly higher in undifferentiated GC [ 22 ]. More recently, it was demonstrated that PDL1 overexpression was a worse prognostic factor in GC [ 19 ].…”

Section: Discussionmentioning

confidence: 97%

“…PDL1 expression has been reported in a wide variety of solid tumors, including lung cancer, hepatocellular carcinoma and intra-hepatic cholangiocarcinoma, gastric, colorectal, pancreatic, ovarian, breast, cervical and oral cancer, head and neck squamous cell carcinomas, nasopharyngeal, esophageal, urothelial and renal cell cancer, nephroblastoma, melanoma and gliomas [ 58 , 59 ]. It has been suggested that CD8 + T cells upregulate PD1 expression and secrete IFN-γ when they encounter tumor antigens, resulting in the upregulation of PDL1 expression on tumor cells and immune cells and the ligation of PDL1 with PD1 will decrease T cell function and create a negative feedback mechanism that decreases antitumor immunity leading to tumorigenesis [ 22 ]. In contradiction with our observation, no statistically significant differences were found with regard to PDL1 mRNA levels within normal and GC specimens as previously verified by Chen et al [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

“…qRT-PCR was performed using 7500 Real-Time PCR system (ThermoFisher Scientific, United States). The primers sequences used were; ARID1A forward 5 ′ -CTTCAACCTCAGTCAGCTCCCA-3′, ARID1A reverse 5′-GGTCACCCACCTCATACTCCTTT-3 ′ ; TP53 forward 5′-TGCGTGTGGAGTATTTGGATG-3′, TP53 reverse 5′-TGGTACAGTCAGAGCCAACCTC-3′; PDL1 forward 5′-ACTGGCATTTGCTGAACGCA-3′, PDL1 reverse 5′- AGACAATTAGTGCAGCCAGGTCT-3′; GAPDH forward 5′- CTCCTCCTGTTCGACAGTCAGC-3; GAPDH reverse, 5′- CCCAATACGACCAAATCCGTT-3 ′ [ 10 , 21 – 22 ]. The GAPDH (housekeeping gene) was used as an internal control.…”

Section: Methodsmentioning

confidence: 99%

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Implication of ARID1A Undercurrents and PDL1, TP53 Overexpression in Advanced Gastric Cancer

Qadir¹,

Majid²,

Khan³

et al. 2021

Pathol. Oncol. Res.

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AT-rich interactive domain-containing protein 1A (ARID1A), TP53 and programmed cell death-ligand 1 (PDL1) are involved in several protein interactions that regulate the expression of various cancer-related genes involved in the progression of the cell cycle, cell proliferation, DNA repair, and apoptosis. In addition, gene expression analysis identified some common downstream targets of ARID1A and TP53. It has been established that tumors formed by ARID1A-deficient cancer cells exhibited elevated PDL1 expression. However, the aberrations in these molecules have not been studied in this population especially in Gastric Cancer (GC). In this backdrop we aimed to investigate the role of the ARID1A mutation and expression of ARID1A, TP53 and PDL1 genes in the etiopathogenesis of Gastric Cancer (GC) in the ethnic Kashmiri population (North India). The study included 103 histologically confirmed GC cases. The mutations, if any, in exon-9 of ARID1A gene was analysed by Polymerase Chain Reaction (PCR) followed by Sanger sequencing. The mRNA expression of the ARID1A, TP53 and PDL1 genes was analysed by Quantitative real time-PCR (qRT-PCR). We identified a nonsense mutation (c.3219; C > T) in exon-9 among two GC patients (∼2.0%), which introduces a premature stop codon at protein position 1073. The mRNA expression of the ARID1A, TP53 and PDL1 gene was significantly reduced in 25.3% and elevated in 47.6 and 39.8% of GC cases respectively with a mean fold change of 0.63, 2.93 and 2.43. The data revealed that reduced mRNA expression of ARID1A and elevated mRNA expression of TP53 and PDL1 was significantly associated with the high-grade and advanced stage of cancer. Our study proposes that ARAD1A under-expression and overexpression of TP53 and PDL1 might be crucial for tumor progression with TP53 and PDL1 acting synergistically.

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Prognostic Significance of PD-1, PD-L1 and CD8 Gene Expression Levels in Gastric Cancer

Cited by 15 publications

References 30 publications

Immune Landscape of Gastric Carcinoma Tumor Microenvironment Identifies a Peritoneal Relapse Relevant Immune Signature

Immune Landscape of Gastric Carcinoma Tumor Microenvironment Identifies a Peritoneal Relapse Relevant Immune Signature

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

Implication of ARID1A Undercurrents and PDL1, TP53 Overexpression in Advanced Gastric Cancer

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