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Supplementary Figures 1-6 from An Empirical Approach Leveraging Tumorgrafts to Dissect the Tumor Microenvironment in Renal Cell Carcinoma Identifies Missing Link to Prognostic Inflammatory Factors

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posted on 2023-04-03, 21:44 authored by Tao Wang, Rong Lu, Payal Kapur, Bijay S. Jaiswal, Raquibul Hannan, Ze Zhang, Ivan Pedrosa, Jason J. Luke, He Zhang, Leonard D. Goldstein, Qurratulain Yousuf, Yi-Feng Gu, Tiffani McKenzie, Allison Joyce, Min S. Kim, Xinlei Wang, Danni Luo, Oreoluwa Onabolu, Christina Stevens, Zhiqun Xie, Mingyi Chen, Alexander Filatenkov, Jose Torrealba, Xin Luo, Wenbin Guo, Jingxuan He, Eric Stawiski, Zora Modrusan, Steffen Durinck, Somasekar Seshagiri, James Brugarolas

Sup. Fig. 1 Simulation analyses show accurate dissection of bulk tumor RNA-Seq data by DisHet. Sup. Fig. 2 Validating immune/stroma component expression dissected by DisHet. Sup. Fig. 3 Comparison of dissection performance of DeMix and DisHet. Sup. Fig. 4 Principal Component Analysis (PCA) shows the clustering of TCGA pan-RCC patients tumors by the tumor-specific genes and eTME-specific genes, respectively. Sup. Fig. 5 CD4 and CD8 immunohistochemistry staining in the Six2-Cre;VhlF/F;Pbrm1F/F and Six2-Cre;VhlF/F;Bap1F/+. Supl. Fig. 6 Clinical manifestations of eTME-NIS patients.

Funding

NIH

Center for Translational Medicine of UT Southwestern

Cancer Prevention and Research Institute of Texas

American Cancer Society

KCP Patient Council

Kidney Cancer Coalition

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ARTICLE ABSTRACT

By leveraging tumorgraft (patient-derived xenograft) RNA-sequencing data, we developed an empirical approach, DisHet, to dissect the tumor microenvironment (eTME). We found that 65% of previously defined immune signature genes are not abundantly expressed in renal cell carcinoma (RCC) and identified 610 novel immune/stromal transcripts. Using eTME, genomics, pathology, and medical record data involving >1,000 patients, we established an inflamed pan-RCC subtype (IS) enriched for regulatory T cells, natural killer cells, TH1 cells, neutrophils, macrophages, B cells, and CD8+ T cells. IS is enriched for aggressive RCCs, including BAP1-deficient clear-cell and type 2 papillary tumors. The IS subtype correlated with systemic manifestations of inflammation such as thrombocytosis and anemia, which are enigmatic predictors of poor prognosis. Furthermore, IS was a strong predictor of poor survival. Our analyses suggest that tumor cells drive the stromal immune response. These data provide a missing link between tumor cells, the TME, and systemic factors.Significance: We undertook a novel empirical approach to dissect the renal cell carcinoma TME by leveraging tumorgrafts. The dissection and downstream analyses uncovered missing links between tumor cells, the TME, systemic manifestations of inflammation, and poor prognosis. Cancer Discov; 8(9); 1142–55. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1047

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    Cancer Discovery

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    Computational MethodsGene expression profilingGenitourinary CancersImmunologyImmune responses to cancer

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