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CCL5-dependent mast cell infiltration into the tumor microenvironment in clear cell renal cell carcinoma patients.

ABSTRACT: We investigated the mechanisms affecting tumor progression and survival outcomes in Polybromo-1-mutated (PBRM1^MUT) clear cell renal cell carcinoma (ccRCC) patients. PBRM1^MUT ccRCC tissues contained higher numbers of mast cells and lower numbers of CD8⁺ and CD4⁺ T cells than tissues from PBRM1^WT ccRCC patients. Hierarchical clustering, pathway enrichment and GSEA analyses demonstrated that PBRM1 mutations promote tumor progression by activating hypoxia inducible factor (HIF)-related signaling pathways and increasing expression of vascular endothelial growth factor family genes. PBRM1^MUT ccRCC tissues also show increased expression of C-C motif chemokine ligand 5 (CCL5). PBRM1-silenced ccRCC cells exhibited greater Matrigel tube formation and cell proliferation than controls. In addition, HMC-1 human mast cells exhibited CCL5-dependent in vitro migration on Transwell plates. High CCL5 expression in PBRM1^MUT ccRCC patients correlated with increased expression of genes encoding IFN-?, IFN-?, IL-6, JAK-STAT3, TNF-?, and NF-?B. Moreover, high CCL5 expression was associated with poorer survival outcomes in ccRCC patients. These findings demonstrate that CCL5-dependent mast cell infiltration promotes immunosuppression within the tumor microenvironment, resulting in tumor progression and adverse survival outcomes in PBRM1^MUT ccRCC patients.

SUBMITTER: Liu T

PROVIDER: S-EPMC7695370 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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CCL5-dependent mast cell infiltration into the tumor microenvironment in clear cell renal cell carcinoma patients.

Liu Tianjie T Xia Qing Q Zhang Haibao H Wang Zixi Z Yang Wenjie W Gu Xiaoyun X Hou Tao T Chen Yule Y Pei Xinqi X Zhu Guodong G He Dalin D Li Lei L Xu Shan S

Aging 20201111 21

We investigated the mechanisms affecting tumor progression and survival outcomes in Polybromo-1-mutated (PBRM1MUT) clear cell renal cell carcinoma (ccRCC) patients. PBRM1MUT ccRCC tissues contained higher numbers of mast cells and lower numbers of CD8+ and CD4+ T cells than tissues from PBRM1WT ccRCC patients. Hierarchical clustering, pathway enrichment and GSEA analyses demonstrated that PBRM1 mutations pr ...[more]

PMID: 33177244

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Project description:BackgroundIt is well known that chronic inflammation can promote the occurrence and progression of cancer. As a type of proinflammatory death, pyroptosis can recast a suitable microenvironment to promote tumor growth. However, the potential role of pyroptosis in clear cell renal cell carcinoma (ccRCC) remains unclear.MethodsThe transcriptome expression profile and mutation profile data of ccRCC with clinical characteristics included in this study were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Consensus clustering was used for clustering. Gene set enrichment analysis (GSEA) analysis were applied to evaluate the biological mechanisms. Single sample gene set enrichment analysis (ssGSEA) was applied for evaluating the proportion of various immune infiltrating cells. The ESTIMATE algorithm was involved to compute the immune microenvironment scores.ResultsAmong the 17 pyroptosis regulators, a total of 15 pyroptosis regulators were differential expressed between tumor and normal tissues, in which 12 of them emerged strong correlations with prognoses. According to the pyroptosis components, the ccRCC patients were divided into four pyroptosis subtypes with different clinical, molecular, and pathway characteristics. Compared with other clusters, cluster B showed the pyroptosis heat phenotype, while cluster D represented the pyroptosis cold phenotype with poor overall survival. In addition, we performed principal component analysis (PCA) on the differential genes between clusters to construct the pyroptosis index. Furthermore, the pyroptosis index was significantly correlated with survival in different tumor mutation statuses and different grades and stages. Besides, the expression of pyroptosis-related regulators was related to the infiltration of immune cells and the expression of immune checkpoints, among which AIM2 was considered as the most significant immune-related pyroptosis regulator. Ultimately, we found that AIM2 was related to the immune activation pathway and was significantly overexpressed in tumor tissues.ConclusionThis study revealed that pyroptosis regulators and pyroptosis index played an important role in the development and prognoses of ccRCC. Moreover, AIM2 can be used as a predictor of the response of immunotherapy. Assessing the pyroptosis patterns may help evaluate the tumor status and guide immunotherapy strategies.

Project description:Previous studies have demonstrated that direct targeting of interstitial cancer-associated fibroblasts (CAF) and tumor fibrosis alone seemed to be an unpromising treatment option for malignant tumors. Therefore, it is necessary to further explore the mechanism of the influence of collagen and tumor fibrosis on the biological behavior of malignant tumors. The current study aimed to explore the effect of intratumor fibrosis on the prognosis of renal clear cell carcinoma (ccRCC) and its mechanism. With the bioinformatic analysis of The Cancer Genome Atlas (TCGA) database (n = 537), the study showed that high Collagen type I α 1 (COL1A1) mRNA expression indicated the poor prognosis of ccRCC patients compared with low expression ones. We further used the Two-photon-excited fluorescence (TPEF)/second harmonic generation (SHG) microscopy to determine the intratumor fibrosis of 68 patients with surgical resection of ccRCC and confirmed that a high fibrosis level in the tumor was associated with a poor prognosis compared with patients with low expression (Progression-Free Survival: p = 0.030). We further measured the protein chips of 640 cytokines in ccRCC specimens and found that several cytokines, including prolactin (PRL), were associated with the degree of fibrosis in the tumor, as confirmed by the prolactin receptor (PRLR) immunohistochemical method. In addition, the study showed that PRLR expression decreased significantly in the ccRCC compared with adjacent normal tissue (p < 0.05). Our research shows that low expression of PRLR predicted the poor survival of the patient. We used the Cell Counting Kit-8 experiment, the transwell and the plate clone formation assay to evaluate the role of PRL in the 7860 and the ACHN cell lines. We found that PRL promoted ccRCC cell proliferation and migration. JAK-STAT3 activation was found in the high prolactin expression group by mass spectrum analysis. This study delineated the fibrosis-based tumor microenvironment characteristics of ccRCC. PRL/PRLR may be involved in the fibrosis process and are essential prognostic risk factors for ccRCC.

Dataset Information

CCL5-dependent mast cell infiltration into the tumor microenvironment in clear cell renal cell carcinoma patients.

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CCL5-dependent mast cell infiltration into the tumor microenvironment in clear cell renal cell carcinoma patients.

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