Dataset Information

Chloride intracellular channel protein 2: prognostic marker and correlation with PD-1/PD-L1 in breast cancer.

ABSTRACT: Immune checkpoint inhibition has emerged as an effective treatment for multiple solid tumors, including advanced-stage breast cancer (BC). During the past decade, the US Food and Drug Administration has approved a number of agents for immune checkpoint blockade (ICB). However, the limited data on monotherapy anti-tumor activity in BC underscores the need for robust predictive biomarker development. Here, we used weighted gene coexpression network analysis of genes differentially expressed between BC and normal tissue to identify genes coexpressed with programmed death-1 (PD-1) and its ligand (PD-L1). Tumor Immune Estimation Resource and Gene Expression Profiling Interaction Analysis were used to assess the relationship between gene expression and the abundance of tumor-infiltrating lymphocytes (TILs). We found that chloride intracellular channel protein 2 (CLIC2) was not only coexpressed with PD-1 and PD-L1, but its increased expression was associated with a favorable prognosis and enrichment of multiple TIL types, particularly CD8+ T cells. These results suggest that CLIC2 is a potentially useful biomarker for identifying BC patients who could benefit from ICB.

SUBMITTER: Xu T

PROVIDER: S-EPMC7521498 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Chloride intracellular channel protein 2: prognostic marker and correlation with PD-1/PD-L1 in breast cancer.

Xu Tao T Wang Zhi Z Dong Menglu M Wu Di D Liao Shujie S Li Xingrui X

Aging 20200911 17

Immune checkpoint inhibition has emerged as an effective treatment for multiple solid tumors, including advanced-stage breast cancer (BC). During the past decade, the US Food and Drug Administration has approved a number of agents for immune checkpoint blockade (ICB). However, the limited data on monotherapy anti-tumor activity in BC underscores the need for robust predictive biomarker development. Here, we used weighted gene coexpression network analysis of genes differentially expressed betwee ...[more]

PMID: 32915772

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Project description:The effects of non-amplification short variant (SV) mutations in CD274 (programmed death-ligand 1 (PD-L1)) on PD-L1 protein expression and immune checkpoint inhibitors (ICPIs) therapy are unknown. Here, we present a retrospective analysis of CD274 mutations detected by comprehensive genomic profiling (CGP) and correlate these results with tumor-cell PD-L1 immunohistochemistry (IHC)-based expression assessment to better understand the relationship between mutations and protein expression of PD-L1. CGP was performed on hybridization-captured, adaptor ligation-based libraries using DNA and/or RNA extracted from 314,631 tumor samples that were sequenced for up to 406 cancer-related genes and select gene rearrangements. PD-L1 IHC was performed on a subset of cases (n=58,341) using the DAKO 22C3 PD-L1 IHC assay and scored with the tumor proportion score (TPS). Overall, the prevalence of CD274 SV mutations was low (0.3%, 1081/314,631) with 577 unique variants. The most common CD274 SV mutations were R260H (n=51), R260C (n=18), R125Q (n=12), C272fs*13 (n=11), R86W (n=10), and R113H (n=10). The prevalence of CD274 mutations varied depending on tumor type with diffuse large B-cell lymphoma (1.9%, 19/997), cutaneous squamous cell carcinoma (1.6%, 14/868), endometrial adenocarcinoma (1.0%, 36/3740), unknown primary melanoma (0.9%, 33/3679), and cutaneous melanoma (0.8%, 32/3874) having the highest frequency of mutations. Of the R260H cases concurrently tested with PD-L1 IHC, most (81.8%, 9/11) had no PD-L1 expression, which contrasts to the five E237K cases where most (80%, 4/5) had PD-L1 expression. In addition, we saw a significantly lower level of PD-L1 expression in samples with a clonal truncating variant (nonsense or frameshift indel) when compared with samples with a subclonal truncating variants (mean: TPS=1 vs TPS=38; p<0.001), and also in clonal versus subclonal missense mutations (mean: TPS=11 vs TPS=22, respectively; p=0.049) CONCLUSIONS: We defined the landscape of CD274 mutations in a large cohort of tumor types that can be used as a reference for examining CD274 mutations as potential resistance biomarkers for ICPI. Furthermore, we presented novel data on the correlation of CD274 mutations and PD-L1 protein expression, providing important new information on the potential functionality of these mutations and can serve as a basis for future research.

Project description:BackgroundHigh expression of integral membrane protein 2A (ITM2A) was reported to be associated with favorable prognosis in several solid tumors including breast cancer. This study aimed to investigate the role of ITM2A in breast cancer, especially in respect to tumor microenvironment.MethodsITM2A expression was evaluated based on qRT-PCR results on breast cancer specimens, as well as TCGA and GEO datasets. The influence of ITM2A expression on breast cancer cell proliferation and tumor growth were evaluated by CCK-8 assay, clonogenic assay, and murine xenograft models. Transwell assay was performed to observe the changes of invasion and migration capacity in breast cancer cells. To determine the biological functions of ITM2A, differentially expressed genes (DEGs) were screened based on RNA-sequencing data of MCF-7 cells overexpressed ITM2A. Then, functional annotation on DEGs was given by Gene Ontology and KEGG analysis. The stimulation on programmed cell death ligand 1 (PD-L1) expression when ITM2A overexpressed was determined by flow cytometry. Meanwhile, the correlation on expression levels between PD-L1 and ITM2A was tested via qRT-PCR on 24 breast cancer tissues, as well as public database.ResultsWe demonstrated that ITM2A was frequently downregulated in breast cancer. Patients with high expression levels of ITM2A had longer overall survival and relapse free survival. Overexpression of ITM2A inhibited proliferation and impaired cells capacity of invasion and migration in vitro and in vivo. The DEGs in breast cancer cells overexpressed ITM2A were found to be associated with immunity responses. Moreover, ITM2A was found to facilitate breast cancer cells to express PD-L1. The correlation between PD-L1 and ITM2A was verified with both qRT-PCR assay and public database. Additionally, it was found that breast cancer had higher ITM2A expression frequently had more tumor-infiltrating lymphocytes (TILs).ConclusionIn summary, we found that high expression of ITM2A reduced the aggressivity of breast cancer cells and had a favorable effect on outcomes of patients with breast cancer. Moreover, ITM2A induced PD-L1 expression in breast cancer cells was accompanied with higher TILs numbers in tumor microenvironment.

Dataset Information

Chloride intracellular channel protein 2: prognostic marker and correlation with PD-1/PD-L1 in breast cancer.

Publications

Chloride intracellular channel protein 2: prognostic marker and correlation with PD-1/PD-L1 in breast cancer.

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