Analysis of VISTA expression and function in renal cell carcinoma highlights VISTA as a potential target for immunotherapy.
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ABSTRACT:
SUBMITTER: Hong S
PROVIDER: S-EPMC6834738 | biostudies-literature | 2019 Nov
REPOSITORIES: biostudies-literature
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Analysis of VISTA expression and function in renal cell carcinoma highlights VISTA as a potential target for immunotherapy.
Hong Shanjuan S Yuan Qing Q Xia Haizhui H Zhu Genzhen G Feng Yu Y Wang Qiang Q Zhang Zhiyin Z He Wei W Lu Jian J Dong Chen C Ni Ling L
Protein & cell 20191101 11
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Project description:IntroductionRenal cell carcinoma (RCC) is primarily managed by surgery with the use of systemic targeted therapy in a metastatic setting. Newer targeted therapeutic options are evolving; Eph-ephrin is a potential new pathway. The therapeutic potential of targeting the EphB4-EphrinB2 pathway has been demonstrated in many solid tumors; however, its expression in RCC has only been evaluated in a few studies with limited cases. We herein determine the immunohistochemical expression of EphrinB2 in RCC.MethodsA tissue microarray comprising 110 cases of different histological subtypes of RCC and 10 normal kidney tissues were stained with monoclonal anti-EphrinB2 antibody (Abcam, AB201512). The tumor and endothelial cells expressing the EphrinB2 were examined and its expression was correlated with sex, histological subtypes, and tumor nodes metastasis (TNM) stage.ResultsTwenty cases of urothelial carcinoma and two unsatisfactory conventional clear cell RCC cases were excluded, and EphrinB2 expression was interpreted in the remaining 88 tumors. EphrinB2 was expressed in 42 out of 88 tumors (47.7%) and was negative in the normal renal parenchyma. There was a statistically significant difference in the expression of EphrinB2 in males (55%) and females (32%). However, no such difference of expression was noted for the histological subtypes and the stages. Half (51%) of Stage 1 (n = 30) and Stage 2 (n = 11) tumors showed EphrinB2 positivity.ConclusionsEphrinB2 is expressed in approximately half of RCC cases. EphrinB2 expression in the early stage cancer might indicate its induction as an early event.
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Project description:Kidney renal papillary cell carcinoma (KIRP) is a common urinary tumor that causes lymph node invasion. Once metastatic, the prognosis is poor and there is a lack of effective early diagnostic markers for this tumor. The expression of CCNB1 in KIRP tumor tissues was significantly higher than that in normal tissues in The Cancer Genome Atlas database with or without the genotype-tissue expression database, and a consistent result was obtained in 32 paired tissues. In addition, CCNB1 expression increased remarkably with the progression of the T and M stages. Moreover, using the online HPA database, we verified that the immunohistochemical scores of CCNB1 in KIRP were higher than those in the normal kidney tissues. The higher expression group of CCNB1 showed a worse prognosis in KIRP. Moreover, the receiver operating characteristic curve, univariate and multivariate analyses, and construction of the column diagram further illustrated that CCNB1 was an independent prognostic factor for KIRP. Meanwhile, CCNB1 could better predict the 1- and 3-year survival rates of KIRP. Six genes were significantly and positively co-expressed with CCNB1. We also found that the CCNB1 high-expression group was enriched in the ECM_RECEPTOR_INTERACTION and FOCAL_ADHESION pathways. Finally, drug sensitivity analysis combined with molecular docking identified 5 targeting drugs with the strongest binding activity to CCNB1. CCNB1 is a potential and reliable biomarker for KIRP diagnosis and can be used to predict the survival of patients with KIRP. The 5 selected drugs targeting CCNB1 may provide new hopes for patients with KIRP metastasis.
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Project description:Agents targeting the B7 family co-inhibitory receptors cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1), or its ligand (PD-L1), have a pivotal role in clinical practice. V-domain Ig suppressor of T-cell activation (VISTA) is a protein highly conserved between species, with a similar amino acid sequence to the B7 family members, characterized by a particularly structural homology to PD-1. It has been counted as an emerging target within the list of novel targetable immune checkpoints in oncology. Physiologically, VISTA exerts a regulatory function on the immune system at several levels, particularly by modulating T cells activation. Its altered activity plays a role in many autoimmune diseases, and its expression has been found to be prognostically implicated in different cancer types in preclinical models. We hereby present the main evidence on the value of VISTA as an immune checkpoint in solid and hematological malignancies. We also review its value as a potential target for cancer immunotherapy, by reporting the results of Phase I and II clinical trials assessing the use of drugs targeting VISTA. The complexity of its pathway, along with some unclear biological aspects concerning its molecular interactions, currently represent a limit to the applicability of VISTA as an effective biomarker for immunotherapy in oncology. A deeper characterization of this immune checkpoint may help defining its value within immune signatures of solid and hematological malignancies, and to design future therapeutic strategies.
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Project description:Feline mammary carcinoma (FMC) is a common neoplasia, showing aggressive clinicopathological features, without viable therapeutic options. The study of tumor microenvironment has gained importance, due to the ability to control tumor progression by regulating the immune response. Considering the lack of knowledge, feline serum VISTA levels from cats with mammary carcinoma were compared with healthy controls, and with serum levels of PD-1/PD-L1, CTLA-4, LAG-3, IL-6, and TNF-α. In parallel, VISTA tumor expression was evaluated in FMC samples. The obtained data revealed that serum VISTA levels were significantly higher in cats presenting HER2-positive (p = 0.0025) or triple-negative subtypes (p = 0.0019), with higher serum levels in luminal A (p = 0.0025) correlated to the presence of metastasis (p = 0.0471). Furthermore, in HER2-positive or triple-negative tumors, correlations were obtained between serum VISTA levels and the serum levels of the above-mentioned molecules. In tumors, VISTA expression revealed a stronger intensity in cancer cells, when compared to TILs (p < 0.0001). Stratifying the samples by subtypes, a higher number of VISTA-positive TILs was observed in the HER2-positive subtype, compared with triple-negative tumors (p = 0.0138). In conclusion, results support the development of therapeutic strategies for HER2-positive and triple-negative FMC subtypes, reinforcing the use of cats as a human oncology model.
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Project description:Immune checkpoint therapy (ICT) has transformed cancer treatment in recent years; however, treatment response is not uniform across tumor types. The tumor immune microenvironment plays a critical role in determining response to ICT; therefore, understanding the differential immune infiltration between ICT-sensitive and ICT-resistant tumor types will help to develop effective treatment strategies. We performed a comprehensive analysis of the immune tumor microenvironment of an ICT-sensitive tumor (melanoma, n = 44) and an ICT-resistant tumor (pancreatic cancer, n = 67). We found that a pancreatic tumor has minimal to moderate infiltration of CD3, CD4, and CD8 T cells; however, the immune infiltrates are predominantly present in the stromal area of the tumor and are excluded from tumoral area compared with melanoma, where the immune infiltrates are primarily present in the tumoral area. Metastatic pancreatic ductal adenocarcinomas (PDACs) had a lower infiltration of total T cells compared with resectable primary PDACs, suggesting that metastatic PDACs have poor immunogenicity. Further, a significantly higher number of CD68+ macrophages and VISTA+ cells (also known as V-domain immunoglobulin suppressor of T cell activation) were found in the pancreatic stromal area compared with melanoma. We identified VISTA as a potent inhibitory checkpoint that is predominantly expressed on CD68+ macrophages on PDACs. These data suggest that VISTA may be a relevant immunotherapy target for effective treatment of patients with pancreatic cancer.
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Project description:Background: Circular RNAs (circRNAs), a novel class of endogenous noncoding RNAs, are involved in a variety of diseases, including several types of cancers. We hypothesized that circRNAs are involved in the tumorigenesis and development of clear cell renal cell carcinoma (ccRCC). Methods: To verify our hypothesis, we explored the circRNA expression profiles in 4 pairs of ccRCC tissues and their adjacent non-carcinoma tissues via microarray analysis. Selected circRNAs were further validated by qPCR. Moreover, hsa_circ_0005875 was selected for further study and the potential clinical values of hsa_circ_0005875 were investigated in 60 pairs of ccRCC tissues and adjacent normal controls. In addition, the role of hsa_circ_0005875 in ccRCC progression were performed using colony formation assay, Transwell assay and Martrigel-Transwell assay respectively. Finally, interactions between the circRNAs and miRNAs were predicted using Arraystar's miRNA target prediction software. Luciferase reporter assays were performed to evaluate the interaction between hsa_circ_0005875 and hsa_miR-145-5p. Results: The microarray data showed 1988 circRNAs were significantly dysregulated circRNAs, including 1033 upregulated and 955 downregulated ones in the ccRCC tissues. Hsa_circ_0005875 was confirmed to be significantly upregulated in the ccRCC tumor tissues and renal carcinoma cells. Further analysis revealed that hsa_circ_0005875 expression was associated with tumor size, pathological TNM stage, histological differentiation, and lymphatic metastasis. Functional experiments demonstrated that overexpression of hsa_circ_0005875 increased proliferation, migration and invasion abilities. Moreover, bioinformatics analysis and luciferase reporter assays suggest that hsa_circ_0005875 may serve as a ceRNA (competing endogenous RNA) of miR-145-5p to relieve the repressive effect of miR-145-5p on target ZEB2. Conclusions: These data indicate that hsa_circ_0005875 might play a role in promoting tumor growth and metastasis and be a potential biomarker of ccRCC.
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Project description:We previously reported that the pVHL-atypical PKC-JunB pathway contributed to promotion of cell invasiveness and angiogenesis in clear cell renal cell carcinoma (ccRCC), and we detected chemokine (C-C motif) ligand-2 (CCL2) as one of downstream effectors of JunB. CCL2 plays a critical role in tumorigenesis in other types of cancer, but its role in ccRCC remains unclear. In this study, we investigated the roles and therapeutic potential of CCL2 in ccRCC. Immunohistochemical analysis of CCL2 expression for ccRCC specimens showed that upregulation of CCL2 expression correlated with clinical stage, overall survival, and macrophage infiltration. For functional analysis of CCL2 in ccRCC cells, we generated subclones of WT8 cells that overexpressed CCL2 and subclones 786-O cells in which CCL2 expression was knocked down. Although CCL2 expression did not affect cell proliferation in vitro, CCL2 overexpression enhanced and CCL2 knockdown suppressed tumor growth, angiogenesis, and macrophage infiltration in vivo. We then depleted macrophages from tumor xenografts by administration of clodronate liposomes to confirm the role of macrophages in ccRCC. Depletion of macrophages suppressed tumor growth and angiogenesis. To examine the effect of inhibiting CCL2 activity in ccRCC, we administered CCL2 neutralizing antibody to primary RCC xenografts established from patient surgical specimens. Inhibition of CCL2 activity resulted in significant suppression of tumor growth, angiogenesis, and macrophage infiltration. These results suggest that CCL2 is involved in angiogenesis and macrophage infiltration in ccRCC, and that CCL2 could be a potential therapeutic target for ccRCC.
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Project description:BackgroundTumor Protein D52-Like 2 (TPD52L2) is a tumor-associated protein that participates in B-cell differentiation. However, the role of TPD52L2 in the pathological process of clear cell renal cell carcinoma (ccRCC) is unclear.MethodsMultiple omics data of ccRCC samples were obtained from public databases, and 5 pairs of ccRCC tissue samples were collected from the operating room. Wilcox, chi-square test, Kaplan-Meier method, receiver operating characteristic curve, regression analysis, meta-analysis, and correlation analysis were used to clarify the relationship of TPD52L2 with clinical features, prognosis, and immune microenvironment. Functional enrichment analysis was performed to reveal the potential pathways in which TPD52L2 participates in the progression of ccRCC. The siRNA technique was used to knockdown in the expression level of TPD52L2 in 786-O cells to verify its effect on ccRCC progression.ResultsFirst, TPD52L2 was found to be upregulated in ccRCC at both mRNA and protein levels. Second, TPD52L2 was significantly associated with poor prognosis and served as an independent prognostic factor. Moreover, TPD52L2 expression was regulated by DNA methylation, and some methylation sites were associated with ccRCC prognosis. Third, TPD52L2 overexpression may participate in the pathological process through various signaling pathways such as cytokine-cytokine receptor interactions, PI3K-Akt, IL-17, Wnt, Hippo signaling pathway, and ECM-receptor interactions. Interestingly, TPD52L2 expression level was also closely related to the abundance of various immune cells, immune checkpoint expression, and TMB. Finally, in vitro experiments confirmed that knocking down TPD52L2 can inhibit the proliferation, migration, and invasion abilities of ccRCC cells.ConclusionThis study for the first time revealed the upregulation of TPD52L2 expression in ccRCC, which is closely associated with poor prognosis of patients and is a potentially valuable therapeutic and efficacy assessment target for immunotherapy.
| S-EPMC10701739 | biostudies-literature
Project description:BackgroundEpigenetic mechanisms play vital roles in the activation, differentiation, and effector function of immune cells. The breast and kidney-expressed chemokine (CXCL14) mainly contributes to the regulation of immune cells. However, its role in shaping the tumor immune microenvironment (TIME) is yet to be elucidated in renal cell carcinoma (RCC).ObjectivesThis study aimed to elucidate the role of CXCL14 in predicting the efficacy of immunotherapy in patients with RCC.MethodsCXCL14 expression and RNA-sequencing, single-cell RNA-sequencing (scRNA-seq), and survival datasets of RCC from public databases were analyzed, and survival was compared between different CXCL14 levels. The correlation between CXCL14 and immune infiltration and human leukocyte antigen (HLA) gene expression was analyzed with TIMER2.0 and gene expression profiling interactive analysis. Institutional scRNA-seq and immunohistochemical staining analyses were used to verify the relationship between CXCL14 expression level and the efficacy of immunotherapy.ResultsCXCL14 was expressed in fibroblast and malignant cells in RCC, and higher expression was associated with better survival. Enrichment analysis revealed that CXCL14 is involved in immune activation, primarily in antigen procession, antigen presentation, and major histocompatibility complex assemble. CXCL14 expression was positively correlated with T-cell infiltration as well as HLA-related gene expression. Among the RCC cohort receiving nivolumab in Checkmate 025, the patients with CXCL14 high expression had better overall survival than those with CXCL14 low expression after immunotherapy. scRNA-seq revealed a cluster of CXCL14+ fibroblast in immunotherapy responders. Immunohistochemistry analysis verified that the patients with high CXCL14 expression had an increased proportion of high CD8 expression simultaneously. The expression level of CXCL14 was associated with CXCR4 expression in RCC.ConclusionCXCL14 expression is associated with immunotherapy response in RCC. It is a promising biomarker for immunotherapy response prediction and may be an effective epigenetic modulator in combination with immunotherapy approaches.
| S-EPMC10752123 | biostudies-literature
Project description:BackgroundNovel immune therapies targeting tumor specific antigens are being developed. Our purpose was to determine expression of the cancer testes antigen NY-ESO-1 in renal cell carcinoma (RCC), as NY-ESO-1 targeting approaches, particularly adoptive cell therapy, have not been evaluated in this disease.MethodsWe employed tissue microarrays containing >300 unique RCC cases and adjacent benign renal tissue to determine NY-ESO-1 expression using a quantitative immunofluorescence method. In addition, we studied NY-ESO-1 expression in 35 matched primary and metastatic RCC specimens to assess concordance between different tumor sites.ResultsNY-ESO-1 was highly expressed in a subset of RCCs. Expression in primary RCC specimens was significantly higher than adjacent normal renal tissue (P<0.0001) and higher in clear cell carcinomas than papillary RCC (P<0.0001). Expression levels in metastatic specimens were higher than in matched primary samples (P=0.0018), and the correlation between the two sites was modest (χ2=3.5, p=0.06).ConclusionsAberrant NY-ESO-1 expression seen in clear cell RCC suggests that NY-ESO-1 targeting approaches should be studied in this disease. Expression is higher in metastatic sites, and discordance between primary and metastatic sites in some patients suggests that patient selection for these therapies should be based on expression in metastatic rather than nephrectomy specimens.
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