Mapping single-cell transcriptomes in the intra-tumoral and associated territories of kidney cancer

Li, Ruoyan; Ferdinand, John R.; Loudon, Kevin; Bowyer, Georgina; Laidlaw, Sean; Muyas, Francesc; Mamanova, Lira; Neves, Joana B.; Bolt, Liam; Fasouli, Eirini S.; Lawson, Andrew; Young, Matthew D.; Hooks, Yvette; Oliver, Thomas R. W.; Butler, Timothy; Armitage, James; Aho, Tev; Riddick, Antony C. P.; Gnanapragasam, Vincent; Welsh, Sarah J.; Meyer, Kerstin B.; Warren, Anne Y.; Tran, Maxine; Stewart, Grant D.; Cortés-Ciriano, Isidro; Behjati, Sam; Clatworthy, Menna R.; Campbell, Peter J.; Teichmann, Sarah A.; Mitchell, Thomas J.

doi:10.1016/j.ccell.2022.11.001

Cited by 83 publications

(63 citation statements)

References 71 publications

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“…To further delineate expression of the chemokines of interest and the cognate receptors at the single-cell level, we reanalyzed a publicly available PDAC dataset ( 49 ), comprising single-cell RNAseq data from 12 RCC samples. Following cell type annotation, re-analysis revealed CXCL9 as well as CXCL10 expression mainly in myeloid cells, whereas CXCL11 was exclusively expressed in tumor cells.…”

Section: Resultsmentioning

confidence: 99%

“…(A) Overview of cellular localization of chemokines (CXCL9/10/11, CXCL13 and XCL1) and the cognate receptors (CXCR3, CXCR5 and XCR1). (B) Dotplot expression analysis of annotated myeloid subpopulations in the dataset ( 49 ) with targets CXCL9/10 and XCR1 demonstrating dendritic cells as the major source of XCR1 and M1 TAMs for CXCL9/10. As a representative member of the chemokine cluster, CXCL9 was further analyzed by flow cytometry.…”

Section: Resultsmentioning

confidence: 99%

“…The respective dataset consisting of samples obtained from 12 patients with RCC was downloaded as AnnData object (h5ad) from previously published studies of Li R. et al. ( 49 ) [Dataset ( 50 )] and imported in Scanpy version 1.9.1. The dataset was controlled for the quality with scanpy by thresholding the number of detected genes (200), counts (2000) and the fraction of mitochondrial reads (<30%).…”

Section: Methodsmentioning

confidence: 99%

“…A neighborhood graph and UMAP embedding was computed based on the scVI latent space. All cell-type annotations were used from the original study ( 49 ). Annotated cell types were confirmed by a set of cell type–specific markers such as, CD3E, CD68, CD8A, CD4, CD79A, KIT, CDH5, ACTA2, EPCAM.…”

Section: Methodsmentioning

confidence: 99%

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A chemokine network of T cell exhaustion and metabolic reprogramming in renal cell carcinoma

Pichler

Siska

Tymoszuk³

et al. 2023

Front. Immunol.

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Renal cell carcinoma (RCC) is frequently infiltrated by immune cells, a process which is governed by chemokines. CD8+ T cells in the RCC tumor microenvironment (TME) may be exhausted which most likely influence therapy response and survival. The aim of this study was to evaluate chemokine-driven T cell recruitment, T cell exhaustion in the RCC TME, as well as metabolic processes leading to their functional anergy in RCC. Eight publicly available bulk RCC transcriptome collectives (n=1819) and a single cell RNAseq dataset (n=12) were analyzed. Immunodeconvolution, semi-supervised clustering, gene set variation analysis and Monte Carlo-based modeling of metabolic reaction activity were employed. Among 28 chemokine genes available, CXCL9/10/11/CXCR3, CXCL13/CXCR5 and XCL1/XCR1 mRNA expression were significantly increased in RCC compared to normal kidney tissue and also strongly associated with tumor-infiltrating effector memory and central memory CD8+ T cells in all investigated collectives. M1 TAMs, T cells, NK cells as well as tumor cells were identified as the major sources of these chemokines, whereas T cells, B cells and dendritic cells were found to predominantly express the cognate receptors. The cluster of RCCs characterized by high chemokine expression and high CD8+ T cell infiltration displayed a strong activation of IFN/JAK/STAT signaling with elevated expression of multiple T cell exhaustion-associated transcripts. Chemokinehigh RCCs were characterized by metabolic reprogramming, in particular by downregulated OXPHOS and increased IDO1-mediated tryptophan degradation. None of the investigated chemokine genes was significantly associated with survival or response to immunotherapy. We propose a chemokine network that mediates CD8+ T cell recruitment and identify T cell exhaustion, altered energy metabolism and high IDO1 activity as key mechanisms of their suppression. Concomitant targeting of exhaustion pathways and metabolism may pose an effective approach to RCC therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A chemokine network of T cell exhaustion and metabolic reprogramming in renal cell carcinoma

Pichler

Siska

Tymoszuk³

et al. 2023

Front. Immunol.

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“…As such, this would complement the work of Li et al . [ 48 ] who studied ccRCC heterogeneity using a multi-region analysis of scRNA-seq and exome sequencing mutational landscapes.…”

Section: Discussionmentioning

confidence: 99%

Extensive intratumor regional epigenetic heterogeneity in clear cell renal cell carcinoma targets kidney enhancers and is associated with poor outcome

et al. 2023

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Background Clear cell renal cell cancer (ccRCC), the 8th leading cause of cancer-related death in the US, is challenging to treat due to high level intratumoral heterogeneity (ITH) and the paucity of druggable driver mutations. CcRCC is unusual for its high frequency of epigenetic regulator mutations, such as the SETD2 histone H3 lysine 36 trimethylase (H3K36me3), and low frequency of traditional cancer driver mutations. In this work, we examined epigenetic level ITH and defined its relationships with pathologic features, aspects of tumor biology, and SETD2 mutations. Results A multi-region sampling approach coupled with EPIC DNA methylation arrays was conducted on a cohort of normal kidney and ccRCC. ITH was assessed using DNA methylation (5mC) and CNV-based entropy and Euclidian distances. We found elevated 5mC heterogeneity and entropy in ccRCC relative to normal kidney. Variable CpGs are highly enriched in enhancer regions. Using intra-class correlation coefficient analysis, we identified CpGs that segregate tumor regions according to clinical phenotypes related to tumor aggressiveness. SETD2 wild-type tumors overall possess greater 5mC and copy number ITH than SETD2 mutant tumor regions, suggesting SETD2 loss contributes to a distinct epigenome. Finally, coupling our regional data with TCGA, we identified a 5mC signature that links regions within a primary tumor with metastatic potential. Conclusion Taken together, our results reveal marked levels of epigenetic ITH in ccRCC that are linked to clinically relevant tumor phenotypes and could translate into novel epigenetic biomarkers.

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Single‐cell and spatial omics unravel the spatiotemporal biology of tumour border invasion and haematogenous metastasis

Cheng,

Cao,

Liu

et al. 2024

Clinical & Translational Med

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Solid tumours exhibit a well‐defined architecture, comprising a differentiated core and a dynamic border that interfaces with the surrounding tissue. This border, characterised by distinct cellular morphology and molecular composition, serves as a critical determinant of the tumour's invasive behaviour. Notably, the invasive border of the primary tumour represents the principal site for intravasation of metastatic cells. These cells, known as circulating tumour cells (CTCs), function as ‘seeds’ for distant dissemination and display remarkable heterogeneity. Advancements in spatial sequencing technology are progressively unveiling the spatial biological features of tumours. However, systematic investigations specifically targeting the characteristics of the tumour border remain scarce. In this comprehensive review, we illuminate key biological insights along the tumour body‐border‐haematogenous metastasis axis over the past five years. We delineate the distinctive landscape of tumour invasion boundaries and delve into the intricate heterogeneity and phenotype of CTCs, which orchestrate haematogenous metastasis. These insights have the potential to explain the basis of tumour invasion and distant metastasis, offering new perspectives for the development of more complex and precise clinical interventions and treatments.

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Mapping single-cell transcriptomes in the intra-tumoral and associated territories of kidney cancer

Cited by 83 publications

References 71 publications

A chemokine network of T cell exhaustion and metabolic reprogramming in renal cell carcinoma

A chemokine network of T cell exhaustion and metabolic reprogramming in renal cell carcinoma

Extensive intratumor regional epigenetic heterogeneity in clear cell renal cell carcinoma targets kidney enhancers and is associated with poor outcome

Single‐cell and spatial omics unravel the spatiotemporal biology of tumour border invasion and haematogenous metastasis

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