A single-cell map of dynamic chromatin landscapes of immune cells in renal cell carcinoma

Kourtis, Nikos; Wang, Qingqing; Wang, Bei; Oswald, Erin; Adler, Christina; Cherravuru, Samvitha; Malahias, Evangelia; Zhang, Lance; Golubov, Jacquelynn; Wei, Qiaozhi; Lemus, Samantha; Ni, Min; Ding, Yueming; Wei, Yi; Atwal, Gurinder S.; Thurston, Gavin; Macdonald, Lynn E.; Murphy, Andrew J.; Dhanik, Ankur; Sleeman, Matthew A.; Tykodi, Scott S.; Skokos, Dimitris

doi:10.1038/s43018-022-00391-0

Cited by 35 publications

(27 citation statements)

References 67 publications

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“…Although a previous study revealed the regulatory dynamics of immune cells in ccRCC ( 21 ), the regulatory characteristics of tumor cells remain unknown at single-cell level. To investigate the characteristics of chromatin regulation in tumor cells, we identified 16 tumor cell subtypes and the chromatin accessibility regions of each cell subtype by using scATAC-seq ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…A previous study has constructed a single-cell map of dynamic chromatin landscapes of immune cells in renal cell carcinoma, which provided a rich resource for understanding the functional states and regulatory dynamics of immune cells in ccRCC (21). However, a more comprehensive single-cell chromatin accessibility landscape of ccRCC with large samples, including tumor cells, needs to be constructed, which may reveal the regulatory characteristics of tumor cells.…”

Section: Construction Of Single-cell Chromatin Accessibility Landscap...mentioning

confidence: 99%

“…In a previous study, the human single-cell atlas of chromatin accessibility was established by scATAC-seq, which provides a foundation for the analysis of gene regulatory programs in human cell types across tissues ( 20 ). In addition, the single-cell chromatin landscape of immune cells in ccRCC has been mapped to provide a rich resource for understanding the functional states and regulatory dynamics of immune cells ( 21 ). However, few scATAC-seq studies have focused on tumor cells, especially on ccRCC.…”

Section: Introductionmentioning

confidence: 99%

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Integrative Single-Cell Analysis Reveals Transcriptional and Epigenetic Regulatory Features of Clear Cell Renal Cell Carcinoma

et al. 2023

Cancer Research

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Clear cell renal cell carcinoma (ccRCC) frequently features a high level of tumor heterogeneity. Elucidating the chromatin landscape of ccRCC at the single-cell level could provide a deeper understanding of the functional states and regulatory dynamics underlying the disease. Here, we performed single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) on 19 ccRCC samples, and whole-exome sequencing was used to understand the heterogeneity between individuals. Single-cell transcriptome and chromatin accessibility maps of ccRCC were constructed to reveal the regulatory characteristics of different tumor cell subtypes in ccRCC. Two lncRNAs (RP11-661C8.2 and CTB-164N12.1) were identified that promoted the invasion and migration of ccRCC, which was validated with in vitro experiments. Taken together, this study comprehensively characterized the gene expression and DNA regulation landscape of ccRCC, which could provide new insights into the biology and treatment of ccRCC.

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Section: Resultsmentioning

confidence: 99%

Section: Construction Of Single-cell Chromatin Accessibility Landscap...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Integrative Single-Cell Analysis Reveals Transcriptional and Epigenetic Regulatory Features of Clear Cell Renal Cell Carcinoma

et al. 2023

Cancer Research

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“…We subsequently applied the UMAP and t-SNE algorithms on the top 30 principal components to visualize the high dimensional scRNA-seq data and 14 clusters were obtained. Previous canonical cell markers [ 19 , 20 , 21 ] and CellMarker 2.0 [ 22 ] helped us to identify seven T cell subsets ( Figure 1 A,E). Namely, exhausted CD8 + T cells, cytotoxic CD8 + T cells, resident memory CD4 + T cells, cluster1-resident memory CD8 + T cells, cluster2-resident memory CD8 + T cells, CD4 + CD25 + FOXP3 + regulatory T cells, and naive CD4 + T cells.…”

Section: Resultsmentioning

confidence: 99%

A New Signature That Predicts Progression-Free Survival of Clear Cell Renal Cell Carcinoma with Anti-PD-1 Therapy

Lin

Cai

et al. 2023

IJMS

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Immunotherapy has greatly improved the survival time and quality of life of patients with renal cell carcinoma, but the benefits are limited to a small portion of patients. There are too few new biomarkers that can be used to identify molecular subtypes of renal clear cell carcinoma and predict survival time with anti-PD-1 treatment. Single-cell RNA data of clear cell renal cell carcinoma (ccRCC) treated with anti-PD-1 were obtained from public databases, then 27,707 high-quality CD4 + T and CD8 + T cells were obtained for subsequent analysis. Firstly, genes set variation analysis and CellChat algorithm were used to explore potential molecular pathway differences and intercellular communication between the responder and non-responder groups. Additionally, differentially expressed genes (DEGs) between the responder and non-responder groups were obtained using the “edgeR” package, and ccRCC samples from TCGA-KIRC (n = 533) and ICGA-KIRC (n = 91) were analyzed by the unsupervised clustering algorithm to recognize molecular subtypes with different immune characteristics. Finally, using univariate Cox analysis, least absolute shrinkage and selection operator (Lasso) regression, and multivariate Cox regression, the prognosis model of immunotherapy was established and verified to predict the progression-free survival of ccRCC patients treated with anti-PD-1. At the single cell level, there are different signal pathways and cell communication between the immunotherapy responder and non-responder groups. In addition, our research also confirms that the expression level of PDCD1/PD-1 is not an effective marker for predicting the response to immune checkpoint inhibitors (ICIs). The new prognostic immune signature (PIS) enabled the classification of ccRCC patients with anti-PD-1 therapy into high- and low-risk groups, and the progression-free survival times (PFS) and immunotherapy responses were significantly different between these two groups. In the training group, the area under the ROC curve (AUC) for predicting 1-, 2- and 3-year progression-free survival was 0.940 (95% CI: 0.894–0.985), 0.981 (95% CI: 0.960–1.000), and 0.969 (95% CI: 0.937–1.000), respectively. Validation sets confirm the robustness of the signature. This study revealed the heterogeneity between the anti-PD-1 responder and non-responder groups from different angles and established a robust PIS to predict the progression-free survival of ccRCC patients receiving immune checkpoint inhibitors.

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“…Though the immune checkpoint blockade (ICB) therapies are emerging anticancer therapy, the response rate is still variable within and across solid tumour types. To gain insights into this, recent studies have focused on the characterisation of genetic and molecular alterations at the tumour and immune cell levels, and whether these alterations can be used as biomarkers to predict response to ICB therapies (39,41,42). For example, the study by Kalaora et al, (17) showed that the IP gene expression can be used as a potential biomarker to predict prognosis and response to ICB therapy in skin melanoma.…”

Section: Discussionmentioning

confidence: 99%

Prognostic association of immunoproteasome expression in solid tumours is governed by the immediate immune environment

Kumar

Dhaka

Sahoo

et al. 2022

Preprint

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Induction of immunoproteasome (IP) expression in tumour cells can enhance antigen presentation and immunogenicity. Recently, overexpression of IP genes has been associated with better prognosis and response to immune checkpoint blockade (ICB) therapies in melanoma. However, the extent of this association in other solid tumour types and how that is influenced by tumour cell-intrinsic and cell-extrinsic factors remains unclear. Here, we address this by exploring the gene expression patterns from bulk and single-cell transcriptomics data of primary tumours (from TCGA and other studies, respectively). We find that the IP expression positively correlates with the constitutive proteasome (CP) across multiple tumour types. Interestingly, both CP and IP are highly expressed in tumour cells closer to the tumour border than the core region. Furthermore, tumours with high IP expression exhibit cytotoxic immune cell infiltration and upregulation of interferon-gamma, TNF alpha and inflammatory response pathways in tumour cells. However, the association of IP expression with overall survival (in TCGA cohort) and response to ICB therapy (in non-TCGA cohorts) is tumour-type specific and is greatly influenced by the immune cell infiltration patterns. The overall survival is better in skin melanoma, breast carcinoma, bladder carcinoma, cervical squamous cell carcinoma, sarcoma, and mesothelioma; while it is poor in uveal melanoma, low-grade glioma and kidney renal clear cell carcinoma. Similarly, the response to ICB therapy is better in skin melanoma, non-small cell lung cancer, breast cancer and thymic carcinoma, while it is worse in oral cancer and renal carcinoma. Together, this suggests that the IP expression combined with the immune infiltration patterns can be used as a biomarker to predict prognosis and response to ICB therapies in solid tumours.

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A single-cell map of dynamic chromatin landscapes of immune cells in renal cell carcinoma

Cited by 35 publications

References 67 publications

Integrative Single-Cell Analysis Reveals Transcriptional and Epigenetic Regulatory Features of Clear Cell Renal Cell Carcinoma

Integrative Single-Cell Analysis Reveals Transcriptional and Epigenetic Regulatory Features of Clear Cell Renal Cell Carcinoma

A New Signature That Predicts Progression-Free Survival of Clear Cell Renal Cell Carcinoma with Anti-PD-1 Therapy

Prognostic association of immunoproteasome expression in solid tumours is governed by the immediate immune environment

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