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Journal of Translational Medicine

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Open Access 01-12-2023 | Research

Cell–cell communications shape tumor microenvironment and predict clinical outcomes in clear cell renal carcinoma

Authors: Liu-xun Chen, Shen-jie Zeng, Xv-dong Liu, Hai-bin Tang, Jia-wu Wang, Qing Jiang

Published in: Journal of Translational Medicine | Issue 1/2023

Abstract

Background

Cell–cell communications of various cell populations within tumor microenvironment play an essential role in primary tumor growth, metastasis evolution, and immune escape. Nevertheless, comprehensive investigation of cell–cell communications in the ccRCC (Clear cell renal carcinoma) microenvironment and how this interplay affects prognosis still remains limited.

Methods

Intercellular communications were characterized by single-cell data. Firstly, we employed “CellChat” package to characterize intercellular communications across all types of cells in microenvironment in VHL mutated and non-mutated samples from 8 patients, respectively. And pseudotime trajectory analyses were performed with monocle analyses. Finally clinical prognosis and immunotherapy efficacy with different landscapes of intercellular interplay are evaluated by TCGA-KIRC and immunotherapy cohort.

Results

Firstly, the VHL phenotype may be related to the intercellular communication landscape. And trajectory analysis reveals the potential relationship of cell–cell communication molecules with T cells and Myeloid cells differentiation. Furthermore, those molecules also correlate with the infiltration of T cells and Myeloid cells. A tumor cluster with highly expressed ligands was defined by quantitative analysis and transcription factor enrichment analysis, which was identified to be pivotal for intercellular communications in tumor microenvironment. Finally, bulk data indicates bulk that different clusters with different intercellular communications have significant predictive value for prognosis and distinguished immunotherapy efficiency.

Conclusions

The intercellular communication landscapes of VHL wild and VHL mutant ccRCC vary. Intercellular communications within the tumor microenvironment also influence T cell and myeloid cell development and infiltration, as well as predict clinical prognosis and immunotherapy efficacy in ccRCC.

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Barata PC, Rini BI. Treatment of renal cell carcinoma: current status and future directions. Cancer J Clin. 2017;67:507–24.CrossRef

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin. 2018;68:394–424.CrossRef

Nickerson ML, Jaeger E, Shi Y, Durocher JA, Mahurkar S, Zaridze D, Matveev V, Janout V, Kollarova H, Bencko V, Navratilova M, Szeszenia-Dabrowska N, Mates D, Mukeria A, Holcatova I, Schmidt LS, Toro JR, Karami S, Hung R, Gerard GF, Linehan WM, Merino M, Zbar B, Boffetta P, Brennan P, Rothman N, Chow W-H, Waldman FM, Moore LE. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res. 2008;14:4726–34.CrossRefPubMedPubMedCentral

Drake CG, Stein MN. The immunobiology of kidney cancer. J Clin Oncol. 2018;36:3547.CrossRef

Yang D, Jones MG, Naranjo S, Rideout WM 3rd, Min KHJ, Ho R, Wu W, Replogle JM, Page JL, Quinn JJ, Horns F, Qiu X, Chen MZ, Freed-Pastor WA, McGinnis CS, Patterson DM, Gartner ZJ, Chow ED, Bivona TG, Chan MM, Yosef N, Jacks T, Weissman JS. Lineage tracing reveals the phylodynamics, plasticity, and paths of tumor evolution. Cell. 2022;23:67.

Joyce JA. Therapeutic targeting of the tumor microenvironment. Cancer Cell. 2005;7:513–20.CrossRefPubMed

Armingol E, Officer A, Harismendy O, Lewis NE. Deciphering cell-cell interactions and communication from gene expression. Nat Rev Genet. 2021;22:71–88.CrossRefPubMed

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.CrossRefPubMed

Liu K, Cui J-J, Zhan Y, Ouyang Q-Y, Lu Q-S, Yang D-H, Li X-P, Yin J-Y. Reprogramming the tumor microenvironment by genome editing for precision cancer therapy. Mol Cancer. 2022;21:345.CrossRef

10.

Lee SJ, Lattouf J-B, Xanthopoulos J, Linehan WM, Bottaro DP, Vasselli JR. Von Hippel-Lindau tumor suppressor gene loss in renal cell carcinoma promotes oncogenic epidermal growth factor receptor signaling via Akt-1 and MEK-1. Eur Urol. 2008;54:845–54.CrossRefPubMedPubMedCentral

11.

Ruf M, Mittmann C, Nowicka AM, Hartmann A, Hermanns T, Poyet C, van den Broek M, Sulser T, Moch H, Schraml P. pVHL/HIF-Regulated CD70 expression is associated with infiltration of CD27(+) lymphocytes and increased serum levels of soluble CD27 in clear cell renal cell carcinoma. Clin Cancer Res. 2015;21:889–98.CrossRefPubMed

12.

Staller P, Sulitkova J, Liszlwan J, Moch H, Oakeley EJ, Krek W. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature. 2003;425:307–11.CrossRefPubMed

13.

Young MD, Mitchell TJ, Braga FAV, Tran MGB, Stewart BJ, Ferdinand JR, Collord G, Botting RA, Popescu D-M, Loudon KW, Vento-Tormo R, Stephenson E, Cagan A, Farndon SJ, Velasco-Herrera MDC, Guzzo C, Richoz N, Mamanova L, Aho T, Armitage JN, Riddick ACP, Mushtaq I, Farrell S, Rampling D, Nicholson J, Filby A, Burge J, Lisgo S, Maxwell PH, Lindsay S, Warren AY, Stewart GD, Sebire N, Coleman N, Haniffa M, Teichmann SA, Clatworthy M, Behjati S. Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors. Science. 2018;361:594.CrossRefPubMedPubMedCentral

14.

Long Z, Sun C, Tang M, Wang Y, Ma J, Yu J, Wei J, Ma J, Wang B, Xie Q, Wen J. Single-cell multiomics analysis reveals regulatory programs in clear cell renal cell carcinoma. Cell Discovery. 2022;8:34.CrossRef

15.

Braun DA, Hou Y, Bakouny Z, Ficial M, Sant’Angelo M, Forman J, Ross-Macdonald P, Berger AC, Jegede OA, Elagina L, Steinharter J, Sun M, Wind-Rotolo M, Pignon J-C, Cherniack AD, Lichtenstein L, Neuberg D, Catalano P, Freeman GJ, Sharpe AH, McDermott DF, Van Allen EM, Signoretti S, Wu CJ, Shukla SA, Choueiri TK. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat Med. 2020;26:909–18.CrossRefPubMedPubMedCentral

16.

Van de Sande B, Flerin C, Davie K, De Waegeneer M, Hulselmans G, Aibar S, Seurinck R, Saelens W, Cannoodt R, Rouchon Q, Verbeiren T, De Maeyer D, Reumers J, Saeys Y, Aerts S. A scalable SCENIC workflow for single-cell gene regulatory network analysis. Nat Protoc. 2020;15:2247–76.CrossRefPubMed

17.

Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, Hoang CD, Diehn M, Alizadeh AA. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12:453.CrossRefPubMedPubMedCentral

18.

Li Q, Li D, Zhang X, Wan Q, Zhang W, Zheng M, Zou L, Elly C, Lee JH, Liu Y-C. E3 Ligase VHL promotes group 2 innate lymphoid cell maturation and function via glycolysis inhibition and induction of interleukin-33 receptor. Immunity. 2018;48:258.CrossRefPubMedPubMedCentral

19.

Jin S, Guerrero-Juarez CF, Zhang L, Chang I, Ramos R, Kuan CH, Myung P, Plikus MV, Nie Q. Inference and analysis of cell-cell communication using Cell Chat. Nat Commun. 2021;12:1088.CrossRefPubMedPubMedCentral

20.

Consonni FM, Bleve A, Totaro MG, Storto M, Kunderfranco P, Termanini A, Pasqualini F, Ali C, Pandolfo C, Sgambelluri F, Grazia G, Santinami M, Maurichi A, Milione M, Erreni M, Doni A, Fabbri M, Gribaldo L, Rulli E, Soares MP, Torri V, Mortarini R, Anichini A, Sica A. Heme catabolism by tumor-associated macrophages controls metastasis formation. Nat Immunol. 2021;22:595.CrossRefPubMed

21.

Long KB, Gladney WL, Tooker GM, Graham K, Fraietta JA, Beatty GL. IFNγ and CCL2 cooperate to redirect tumor-infiltrating monocytes to degrade fibrosis and enhance chemotherapy efficacy in pancreatic carcinoma. Cancer Discov. 2016;6:400–13.CrossRefPubMedPubMedCentral

22.

Aibar S, González-Blas CB, Moerman T, Huynh-Thu VA, Imrichova H, Hulselmans G, Rambow F, Marine J-C, Geurts P, Aerts J, van den Oord J, Atak ZK, Wouters J, Aerts S. SCENIC: single-cell regulatory network inference and clustering. Nat Methods. 2017;14:1083–6.CrossRefPubMedPubMedCentral

23.

Lou E, Gholami S, Romin Y, Thayanithy V, Fujisawa S, Desir S, Steer CJ, Subramanian S, Fong Y, Manova-Todorova K, Moore MAS. Imaging tunneling membrane tubes elucidates cell communication in tumors. Trends Cancer. 2017;3:678–85.CrossRefPubMed

24.

Chen W, Hill H, Christie A, Kim MS, Holloman E, Pavia-Jimenez A, Homayoun F, Ma Y, Patel N, Yell P, Hao G, Yousuf Q, Joyce A, Pedrosa I, Geiger H, Zhang H, Chang J, Gardner KH, Bruick RK, Reeves C, Hwang TH, Courtney K, Frenkel E, Sun X, Zojwalla N, Wong T, Rizzi JP, Wallace EM, Josey JA, Xie Y, Xie X-J, Kapur P, McKay RM, Brugarolas J. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature. 2016;539:112.CrossRefPubMedPubMedCentral

25.

Bi K, He MX, Bakouny Z, Kanodia A, Napolitano S, Wu J, Grimaldi G, Braun DA, Cuoco MS, Mayorga A, DelloStritto L, Bouchard G, Steinharter J, Tewari AK, Vokes NI, Shannon E, Sun M, Park J, Chang SL, McGregor BA, Haq R, Denize T, Signoretti S, Guerriero JL, Vigneau S, Rozenblatt-Rosen O, Rotem A, Regev A, Choueiri TK, Van Allen EM. Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma. Cancer Cell. 2021;39:649.CrossRefPubMedPubMedCentral

Title: Cell–cell communications shape tumor microenvironment and predict clinical outcomes in clear cell renal carcinoma
Authors: Liu-xun Chen
Shen-jie Zeng
Xv-dong Liu
Hai-bin Tang
Jia-wu Wang
Qing Jiang
Publication date: 01-12-2023
Publisher: BioMed Central
Published in: Journal of Translational Medicine / Issue 1/2023
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-022-03858-x

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