Dataset Information

Changes in Expression of Multiple Checkpoint Molecules and Infiltration of Tumor Immune Cells after Neoadjuvant Chemotherapy in Gastric Cancer.

ABSTRACT: It remains unclear that how tumor immune micro-environment will change following neoadjuvant chemotherapy (NACT) in locally advanced gastric cancer (LAGC). In this study, we aimed to characterize the changes in tumor-infiltrating immune cells and checkpoint molecules following NACT and investigate the prognostic value of these changes in LAGC. Paired tumor samples (pre-NACT and post-NACT) of 60 patients were retrospectively identified and analyzed by multiplex immunohistochemistry with a panel including CD4, CD8, FOXP3, PD-1, PD-L1, and TIM3. Following NACT, the overall median expression levels of CD4, CD8, PD1, PD-L1 and TIM3 were significantly increased (P = 0.008 for PD-L1 and P < 0.001 for all the other markers), while the median FOXP3 expression level remained stable (P = 0.120). Individually, the majority of patients presented increased expression of the markers, while 8.5%, 11.9%, 16.9%, 25.4%, 22.0% and 42.2% of patients had decreased expression of CD4, CD8, PD-1, PD-L1, TIM3 and FOXP3, respectively. Changes in expression between baseline and post-NACT of TIM3, PD-1, and PD-L1 showed strongly positive pairwise correlations with each other (P < 0.001). Multivariate analysis demonstrated that high upregulation levels of CD8 (HR = 0.73, P = 0.028), PD-1 (HR = 0.76, P = 0.027), and PD-L1 (HR = 0.67, P = 0.038) following NACT were beneficial prognostic factors of OS. NACT increase the expression of multiple checkpoint molecules and infiltration of CD4+, CD8+ immune cells in LAGC with the levels of changes in checkpoint molecules positively related with each other. This may raise the possibility of applying immunotherapy with chemotherapy or even dual checkpoint inhibitors in LAGC.

SUBMITTER: Yu Y

PROVIDER: S-EPMC6584940 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Changes in Expression of Multiple Checkpoint Molecules and Infiltration of Tumor Immune Cells after Neoadjuvant Chemotherapy in Gastric Cancer.

Yu Yue Y Ma Xiaopeng X Zhang Yanjuan Y Zhang Yun Y Ying Jianming J Zhang Wen W Zhong Qiaofeng Q Zhou Aiping A Zeng Yixin Y

Journal of Cancer 20190602 12

It remains unclear that how tumor immune micro-environment will change following neoadjuvant chemotherapy (NACT) in locally advanced gastric cancer (LAGC). In this study, we aimed to characterize the changes in tumor-infiltrating immune cells and checkpoint molecules following NACT and investigate the prognostic value of these changes in LAGC. Paired tumor samples (pre-NACT and post-NACT) of 60 patients were retrospectively identified and analyzed by multiplex immunohistochemistry with a panel i ...[more]

PMID: 31258783

Similar Datasets

Project description:BackgroundWe aimed to investigate clinical implications of specific soluble immune checkpoint molecules (sICMs) in locally advanced rectal cancer (LARC) patients treated with neoadjuvant chemoradiotherapy (nCRT).MethodsWe prospectively enrolled 30 LARC patients treated with nCRT and collected blood samples from them before, during, and after nCRT for prospective studies. Immune checkpoints often refer to T cell surface molecules influencing the immune response. Immune checkpoints, in the form of a soluble monomeric form, is widely present in blood. In the study, eight immune checkpoint-related plasma proteins, including programmed death-ligand 1 (PD-L1), CD80, CD86, CD28, CD27, glucocorticoid-induced tumor necrosis factor receptor (GITR), GITR ligand (GITRL), and inducible T-cell costimulator (ICOS), were measured using the Luminex platform. Two independent pathologists categorized patients as the good responders and the poor responders according to Dworak tumor regression grade (TRG).ResultsOf the 30 patients, the levels of sPD-L1, sCD80, sCD86, sCD28, sGITR, sGITRL, sCD27, and sICOS decreased during nCRT (Pre-nCRT vs. During-nCRT, all p<0.05) but were restored after nCRT treatment (Pre-nCRT vs. Post-nCRT, all p>0.05). In the 14 good responders, the levels of sICMs, other than sGITR (p=0.081) and sGITRL (p=0.071), decreased significantly during nCRT (Pre-nCRT vs. During-nCRT, p<0.05), but they were all significantly increased after nCRT (During-nCRT vs. Post-nCRT, all p<0.05). In the 16 poor responders, only sCD80 was significantly reduced during nCRT (Pre-nCRT vs. During-nCRT, p<0.05), and none was significantly increased after nCRT (During-nCRT vs. Post-nCRT, all p<0.05). High levels of sICMs before nCRT were associated with poor response (all OR≥1). The Pre-model that incorporated the 8 sICMs before nCRT yielded a good predictive value (AUC, 0.848) and was identified as an independent predictor of treatment response (OR, 2.62; 95% CI, 1.11-6.18; p=0.027).ConclusionOur results suggest chemoradiotherapy could influence the change of sPD-L1, sCD80, sCD86, sCD28, sGITR, sGITRL, sCD27, and sICOS in patients with LARC. The levels of the majority of soluble immune checkpoint molecules were reduced during nCRT and then restored at the end of nCRT, particularly in patients who responded well to nCRT. Combined baseline sICMs can be developed to predict treatment response.

Project description:Diffuse glioma is one of the most prevalent malignancies of the brain, with high heterogeneity of tumor-infiltrating immune cells. However, immune-associated subtypes of diffuse glioma have not been determined, nor has the effect of different immune-associated subtypes on disease prognosis and immune infiltration of diffuse glioma patients. We retrieved the expression profiles of immune-related genes from The Cancer Genome Atlas (TCGA) (n = 672) and GSE16011 (n = 268) cohorts and used them to identify subtypes of diffuse glioma via Consensus Cluster Plus analysis. We used the limma, clusterProfiler, ESTIMATE, and survival packages of R for differential analysis, functional enrichment, immune and stromal score evaluation respectively in three subtypes, and performed log-rank tests in immune subtypes of diffuse glioma. The immune-associated features of diffuse glioma in the two cohorts were characterized via bioinformatic analyses of the mRNA expression data of immune-related genes. Three subtypes (C1–3) of diffuse glioma were identified from TCGA data, and were verified using the GSE16011 cohort. We then evaluated their immune characteristics and clinical features. Our mRNA profiling analyses indicated that the different subtypes of diffuse glioma presented differential expression profile of specific genes and signal pathways in the TCGA cohort. Patients with subtype C1, who were mostly diagnosed with grade IV glioma, had poorer outcomes than patients with subtype C2 or C3. Subtype C1 was characterized by a higher degree of immune cell infiltration as estimated by GSVA, and more frequent wildtype IDH1. By contrast, subtype C3 included more grade II and IDH1-mutated glioma, and was associated with more infiltration of CD4+T cells. Most subtype C2 had the features between subtypes C1 and C3. Meanwhile, immune checkpoints and their ligand molecules, including PD1/(PD-L1/PDL2), CTLA4/(CD80/CD86), and B7H3/TLT2, were significantly upregulated in subtype C1 and downregulated in subtype C3. In addition, patients with subtype C1 exhibited more frequent gene mutations. Univariate and multivariate Cox regression analyses revealed that diffuse glioma subtype was an effective, independent, and better prognostic factor. Therefore, we established a novel immune-related classification of diffuse glioma, which provides potential immunotherapy targets for diffuse glioma.

Dataset Information

Changes in Expression of Multiple Checkpoint Molecules and Infiltration of Tumor Immune Cells after Neoadjuvant Chemotherapy in Gastric Cancer.

Publications

Changes in Expression of Multiple Checkpoint Molecules and Infiltration of Tumor Immune Cells after Neoadjuvant Chemotherapy in Gastric Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets