Seeing the forest for the trees—single-cell atlases link CD8+ T cells and macrophages to disease progression and treatment response in kidney cancer

Koh, Mei Yee; Sayegh, Nicolas; Agarwal, Neeraj

doi:10.1016/j.ccell.2021.03.008

Cited by 23 publications

(15 citation statements)

References 7 publications

(6 reference statements)

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“…With the increase in the novel treatment options for ccRCC, promising biomarkers for monitoring the ccRCC prognosis are urgently needed (22). Disorders of FRGs have been reported in numerous malignant tumors, suggesting a vital role of FRGs in tumor progression (23,24).…”

Section: Discussionmentioning

confidence: 99%

A New Prognostic Risk Signature of Eight Ferroptosis-Related Genes in the Clear Cell Renal Cell Carcinoma

et al. 2021

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Clear cell renal cell carcinoma (ccRCC) is the most common renal cell carcinoma and has poor prognosis in the locally advanced stage. Ferroptosis, a relatively new type of cell death, has gained significant attention in recent years. This study aimed to explore the prognostic value of ferroptosis-related genes (FRGs) in ccRCC. In this study, 50 differentially expressed FRGs between ccRCC and adjacent normal kidney tissues were identified, 26 of them correlated with overall survival (OS) (P <0.05). Eight optimal FRGs were selected by Lasso regression and multivariate Cox regression analysis, and used to construct a new prognostic risk signature to predict the prognosis of ccRCC patients. In addition, the signature passed the validation of prognostic survival analyses by a significant margin, and the risk score was identified as an independent prognostic marker via Cox regression analyses. Further studies indicated that the signature was significantly correlated with immune cell infiltration. Moreover, the levels of eight FRGs were examined in ccRCC. Collectively, the 8-FRG prognostic risk signature helps the clinicians predict the prognosis and OS of the patients, and standardize prognostic assessments.

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Section: Discussionmentioning

confidence: 99%

A New Prognostic Risk Signature of Eight Ferroptosis-Related Genes in the Clear Cell Renal Cell Carcinoma

et al. 2021

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“…High immune score and ESTIMATE scores have been associated with worse prognosis ( 36 , 37 ). Additionally, the high infiltration levels of exhausted CD8 + T cells and immunosuppressive M2-like macrophages have been reported in advanced renal disease ( 8 ), suggesting that immune scores could indicate progressive T cell dysfunction in patients with ccRCC. This suggestion could also be used to explain a worse prognosis in patients with ccRCC that show a high immune score.…”

Section: Discussionmentioning

confidence: 98%

“…However, a comprehensive analysis of the effect of clinicopathological features on survival in patients treated with first-line immune checkpoint inhibitors and tyrosine kinase inhibitors for ccRCC can aid in clinical decision-making ( 4 ) as their efficacy remains limited ( 5 – 7 ). Few patients treated with immune-based combinations displayed unresponsive reactions and intrinsic or acquired resistance ( 8 ). A recent study showed that tumour and tumour-infiltrating cells are involved in drug resistance or unresponsiveness to cancer treatment strategies ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of Ligand-Receptor Pairs Associated With Tumour Characteristics in Clear Cell Renal Cell Carcinoma

et al. 2022

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The tumour microenvironment (TME) of clear cell renal cell carcinoma (ccRCC) comprises multiple cell types, which promote tumour progression and modulate drug resistance and immune cell infiltrations via ligand-receptor (LR) interactions. However, the interactions, expression patterns, and clinical relevance of LR in the TME in ccRCC are insufficiently characterised. This study characterises the complex composition of the TME in ccRCC by analysing the single-cell sequencing (scRNA-seq) data of patients with ccRCC from the Gene expression omnibus database. On analysing the scRNA-seq data combined with the cancer genome atlas kidney renal clear cell carcinoma (TCGA-KIRC) dataset, 46 LR-pairs were identified that were significantly correlated and had prognostic values. Furthermore, a new molecular subtyping model was proposed based on these 46 LR-pairs. Molecular subtyping was performed in two ccRCC cohorts, revealing significant differences in prognosis between the subtypes of the two ccRCC cohorts. Different molecular subtypes exhibited different clinicopathological features, mutational, pathway, and immune signatures. Finally, the LR.score model that was constructed using ten essential LR-pairs that were identified based on LASSO Cox regression analysis revealed that the model could accurately predict the prognosis of patients with ccRCC. In addition, the differential expression of ten LR-pairs in tumour and normal cell lines was identified. Further functional experiments showed that CX3CL1 can exert anti-tumorigenic role in ccRCC cell line. Altogether, the effects of immunotherapy were connected to LR.scores, indicating that potential medications targeting these LR-pairs could contribute to the clinical benefit of immunotherapy. Therefore, this study identifies LR-pairs that could be effective biomarkers and predictors for molecular subtyping and immunotherapy effects in ccRCC. Targeting LR-pairs provides a new direction for immunotherapy regimens and prognostic evaluations in ccRCC.

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“…Previous studies suggested that the activation of potassium channels could affect the immune function of macrophages via NLRP3 ( Drinkall et al, 2022 ). In contrast, macrophages can reshape the tumor microenvironment of ccRCC and thus influence tumor immunity ( Koh et al, 2021 ; Dong et al, 2022 ). There might be some important associations between KCJN16 regulation of potassium channels and macrophages affecting tumor immunity.…”

Section: Discussionmentioning

confidence: 99%

The Ion Channel-Related Gene Signatures Correlated With Diagnosis, Prognosis, and Individualized Treatment in Patients With Clear Cell Renal Cell Carcinoma

et al. 2022

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Background: Early detection and precise prognostic evaluation of clear cell renal cell carcinoma (ccRCC) are crucial for patient life expectancy. Ion channel-related genes (ICRGs) are of great diagnostic and prognostic value as components that maintain the normal structure of the kidney. Therefore, we systematically explored the diagnostic, prognostic, and therapeutic value of ICRGs in ccRCC using the multi-database.Methods: RNA transcriptome profiles and clinical data of ccRCC patients were extracted and integrated from public databases including The Cancer Genome Atlas, ICGC, GEO, and E-MTAB databases. Ion channel-related genes were obtained from the literature collection. The diagnostic signature was performed using the LASSO and SVM-REF analyses. Meanwhile, the prognostic signature was conducted using the LASSO analyses. Molecular subtyping was performed using the ConsensusClusterPlus and the corresponding therapeutic targets were evaluated using the pRRophetic package. In addition, a prognostic nomogram was constructed based on the results of cox regression analyses.Results: We successfully constructed diagnostic signatures for five ICRGs and prognostic signatures for 10 ICRGs with AUC values greater than 0.7, showing good predictive performance. Based on the median risk score, we found that high-risk patients had a significantly worse prognosis. We also divided ccRCC patients into two clusters according to prognostic ICRGs, and there was a significant survival outcome between the two clusters and different sensitivity to diverse clinical therapeutic strategies. Meanwhile, we constructed a nomogram based on clinical molecules and signatures, and its predictive efficacy was better than the signature or the present tumor-node-metastasis staging system.Conclusion: In this study, we established useful signatures for early detection, prognosis evaluation, and individualized treatment for ccRCC. Moreover, KCNJ16 deserves to be explored comprehensively in the future.

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Seeing the forest for the trees—single-cell atlases link CD8+ T cells and macrophages to disease progression and treatment response in kidney cancer

Cited by 23 publications

References 7 publications

A New Prognostic Risk Signature of Eight Ferroptosis-Related Genes in the Clear Cell Renal Cell Carcinoma

A New Prognostic Risk Signature of Eight Ferroptosis-Related Genes in the Clear Cell Renal Cell Carcinoma

Identification of Ligand-Receptor Pairs Associated With Tumour Characteristics in Clear Cell Renal Cell Carcinoma

The Ion Channel-Related Gene Signatures Correlated With Diagnosis, Prognosis, and Individualized Treatment in Patients With Clear Cell Renal Cell Carcinoma

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