Tumor-associated macrophage-derived chemokine CCL5 facilitates the progression and immunosuppressive tumor microenvironment of clear cell renal cell carcinoma

Xu, Wenhao; Wu, Yuhao; Liu, Wangrui; Anwaier, Aihetaimujiang; Tian, Xi; Su, Jiaqi; Huang, Haiyang; Wei, Gaomeng; Qu, Yuanyuan; Zhang, Ye; Ye, Dingwei

doi:10.7150/ijbs.74647

Cited by 47 publications

(28 citation statements)

References 53 publications

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“…It can contribute to the deterioration of prognosis in breast cancer patients by interacting with CCR3 and can also interact with CCR5 to affect the progression and metastasis of hepatocellular carcinoma(Singh et al 2020; Yamaguchi et al 2021). Tumor-associated macrophages (TAMs) dominate the evolution and outcomes of cancers by perturbing the tumor microenvironment (TME) (Galon & Bruni 2020).CCL5 derived from TAMs can activate the β-catenin/STAT3 signaling, so as to mediate the epithelial-mesenchymal transition (EMT) process, resulting in distant metastasis and prostate cancer stem cells self-renewal in prostatic cancer (Xu et al 2022). In ccRCC studies, CCL5 was found to be highly expressed in ccRCC patients with a poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

Identification of key genes CCL5, PLG, LOX and C3 in clear cell renal cell carcinoma through integrated bioinformatics analysis

Xie,

邓,

Zhao

et al. 2023

Preprint

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Background Clear Cell Renal Cell Carcinoma (ccRCC) is a malignant tumor with high mortality and recurrence rates and the molecular mechanism of ccRCC genesis reminds unclear. In this study, we screen out several key genes associated with the prognosis of ccRCC by using integrated bioinformatics. Methods Two ccRCC expression profiles were downloaded from GEO and one dataset was gained from TCGA. RRA method was used to analyze the three datasets to gain integrated differentially expressed gene (DEGs) by comparing ccRCC with normal tissues. The GO functional annotation and KEGG pathway analysis were performed to analyze the potential functions of these DEGs. The STRING and Cytoscape were used to construct PPI network and module analyses to screen the hub genes. The expression of hub genes was analyzed using GEPIA, followed by RT-qPCR and IHC to validate the expression of hub genes between ccRCC and adjacent normal tissues. Finally, the prognostic value of these hub genes for ccRCC patients were identified by K-M plotter. Result 125 DEGs were identified by using the limma package and RRA method, which include 62 up-expressed genes and 63 down-expressed genes.GO analysis showed that the up-expressed genes were primarily enriched in signal transduction, immune response and cell-cell signaling. The down-expressed genes were primarily enriched in ion transmembrane transport, excretion and transport. The top five enriched pathways gained from the KEGG pathway analysis were complement and coagulation cascades, aldosterone-regulated sodium reabsorption, collecting duct acid secretion, PPAR signaling pathway and prion diseases. K-M plotter and GEPIA database were utilized to make clear that CCL5, LOX and C3 are not only up-expressed in ccRCC, but also had a connection with the poor prognosis of ccRCC. PLG is down-expressed in ccRCC, which associated with the better prognosis of ccRCC. RT-qPCR and IHC assays also confirmed the differential expression of these four hub genes in paired ccRCC and adjacent normal tissues. Conclusion These findings manifest that CCL5, LOX, C3 and PLG may play key roles in the progression and prognosis of ccRCC, which will be helpful for further studies to find the potential therapeutic targets and underlying mechanisms of ccRCC.

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Section: Discussionmentioning

confidence: 99%

Identification of key genes CCL5, PLG, LOX and C3 in clear cell renal cell carcinoma through integrated bioinformatics analysis

Xie,

邓,

Zhao

et al. 2023

Preprint

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“…These multiplex stained slides were scanned through the Vectra Polaris Quantitative Pathology Imaging System (Akoya Biosciences) at 20 nm wavelength intervals from 440 to 780 nm, producing a single image using inForm v.2.4.8 (Akoya Biosciences) to quantify the different biomarkers in each cell 60,61 . The quantity of various cell populations was expressed as both the number of stained cells per square millimeter and as the percentage of positively stained cells among all nucleated cells, following the manufacturer's instructions 59–61 …”

Section: Methodsmentioning

confidence: 99%

“…The mIHC process utilized the Akoya OPAL Polaris 7‐Color Automation IHC kit (NEL871001KT) with two distinct panels (Panel 1: CD8, CK, CD68, CD163, PD‐1, PD‐L1, DAPI; Panel 2: CD3, CK, CD56, CD20, CD4, FoxP3, and DAPI) as depicted in Figure 4A. First, a total of 63 tissue samples were initially deparaffinized in a BOND RX system (Leica Biosystems) and subjected to staining with specific primary antibodies 59–61 . The slides, following the primary antibody incubation, were then treated with secondary antibodies labeled by horseradish peroxidase (HRP) and corresponding reactive Opal fluorophores based on the tyramide signal amplification principle 60,61 .…”

Section: Methodsmentioning

confidence: 99%

“…60,61 The quantity of various cell populations was expressed as both the number of stained cells per square millimeter and as the percentage of positively stained cells among all nucleated cells, following the manufacturer's instructions. [59][60][61] For the evaluation of DCs in relation to TLS maturation, 75 ccRCC slides were co-stained for CD20, CD21, CD23, CD45, DC-LAMP, pan-CK, and DAPI. All dense lymphocytic aggregates and areas exhibiting DC-LAMP signal were imaged and analyzed using seven-color mIF.…”

Section: Mihc and Mif Staining Assaysmentioning

confidence: 99%

“…First, a total of 63 tissue samples were initially deparaffinized in a BOND RX system (Leica Biosystems) and subjected to staining with specific primary antibodies. [59][60][61] The slides, following the primary antibody incubation, were then treated with secondary antibodies labeled by horseradish peroxidase (HRP) and corresponding reactive Opal fluorophores based on the tyramide signal amplification principle. 60,61 Slides bound with primary and secondary antibodies but excluding fluorophores served as negative controls to gauge autofluorescence.…”

Section: Mihc and Mif Staining Assaysmentioning

confidence: 99%

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Unveiling the impact of tertiary lymphoid structures on immunotherapeutic responses of clear cell renal cell carcinoma

Xu,

Lu,

Tian

et al. 2024

MedComm

Self Cite

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Tertiary lymphoid structures (TLS) are organized aggregates of immune cells that form under pathological conditions. However, the predictive value of TLS in clear cell renal cell carcinoma (ccRCC) for immunotherapies remains unclear. We comprehensively assessed the implications for prognosis and immunological responses of the TLS spatial and maturation heterogeneity in 655 ccRCC patients. A higher proportion of early‐TLS was found in peritumoral TLS, while intratumoral TLS mainly comprised secondary follicle‐like TLS (SFL‐TLS), indicating markedly better survival. Notably, presence of TLS, especially intratumoral TLS and SFL‐TLS, significantly correlated with better survival and objective reflection rate for ccRCC patients receiving anti‐Programmed Cell Death Protein‐1 (PD‐1)/Programmed Cell Death‐Ligand‐1 (PD‐L1) immunotherapies. In peritumoral TLS cluster, primary follicle‐like TLS, the proportion of tumor‐associated macrophages, and Treg infiltration in the peritumoral regions increased prominently, suggesting an immunosuppressive tumor microenvironment. Interestingly, spatial transcriptome annotation and multispectral fluorescence showed that an abundance of mature plasma cells within mature TLS has the capacity to produce IgA and IgG, which demonstrate significantly higher objective response rates and a superior prognosis for ccRCC patients subjected to immunotherapy. In conclusion, this study revealed the implications of TLS spatial and maturation heterogeneity on the immunological status and clinical responses, allowing the improvement of precise immunotherapies of ccRCC.

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Exosomes secreted by ST3GAL5^high cancer cells promote peritoneal dissemination by establishing a premetastatic microenvironment

Horie,

Takagane,

Itoh

et al. 2023

Molecular Oncology

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Peritoneal dissemination of cancer affects patient survival. The behavior of peritoneal mesothelial cells (PMCs) and immune cells influences the establishment of a microenvironment that promotes cancer cell metastasis in the peritoneum. Here, we investigated the roles of lactosylceramide alpha‐2,3‐sialyltransferase (ST3G5; also known as ST3GAL5 and GM3 synthase) in the exosome‐mediated pre‐metastatic niche in peritoneal milky spots (MSs). Exosomes secreted from ST3G5high cancer cells (ST3G5high‐cExos) were found to contain high levels of hypoxia‐inducible factor 1‐alpha (HIF1α) and accumulated in MSs via uptake in macrophages (MΦs) owing to increased expression of sialic acid binding Ig like lectin 1 (CD169; also known as SIGLEC1). ST3G5high‐cExos induced pro‐inflammatory cytokines and glucose metabolic changes in MΦs, and the interaction of these MΦs with PMCs promoted mesothelial–mesenchymal transition (MMT) in PMCs, thereby generating αSMA+ myofibroblasts. ST3G5high‐cExos also increased the expression of immune checkpoint molecules and T cell exhaustion in MSs, which accelerated metastasis to the omentum. These events were prevented following ST3G5 depletion in cancer cells. Mechanistically, ST3G5high‐cExos upregulated chemokines, including CC‐chemokine ligand 5 (CCL5), in recipient MΦs and dendritic cells (DCs), which induced MMT and immunosuppression via activation of signal transducer and activator of transcription 3 (STAT3). Maraviroc, a C‐C chemokine receptor type 5 (CCR5) antagonist, prevented ST3G5high‐cExo‐mediated MMT, T cell suppression and metastasis in MSs. Our results suggest ST3G5 as a suitable therapeutic target for preventing cExo‐mediated peritoneal dissemination.

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Tumor-associated macrophage-derived chemokine CCL5 facilitates the progression and immunosuppressive tumor microenvironment of clear cell renal cell carcinoma

Cited by 47 publications

References 53 publications

Identification of key genes CCL5, PLG, LOX and C3 in clear cell renal cell carcinoma through integrated bioinformatics analysis

Identification of key genes CCL5, PLG, LOX and C3 in clear cell renal cell carcinoma through integrated bioinformatics analysis

Unveiling the impact of tertiary lymphoid structures on immunotherapeutic responses of clear cell renal cell carcinoma

Exosomes secreted by ST3GAL5^high cancer cells promote peritoneal dissemination by establishing a premetastatic microenvironment

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Tumor-associated macrophage-derived chemokine CCL5 facilitates the progression and immunosuppressive tumor microenvironment of clear cell renal cell carcinoma

Cited by 47 publications

References 53 publications

Identification of key genes CCL5, PLG, LOX and C3 in clear cell renal cell carcinoma through integrated bioinformatics analysis

Identification of key genes CCL5, PLG, LOX and C3 in clear cell renal cell carcinoma through integrated bioinformatics analysis

Unveiling the impact of tertiary lymphoid structures on immunotherapeutic responses of clear cell renal cell carcinoma

Exosomes secreted by ST3GAL5high cancer cells promote peritoneal dissemination by establishing a premetastatic microenvironment

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Exosomes secreted by ST3GAL5^high cancer cells promote peritoneal dissemination by establishing a premetastatic microenvironment