By leveraging tumorgraft (PDX) RNA-Seq 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 Tregs, NK 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.
Cancer discovery. 2018 Jun 08 [Epub ahead of print]
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
Department of Clinical Sciences, University of Texas Southwestern Medical Center ., Department of Clinical Sciences, University of Texas Southwestern Medical Center., Department of Pathology, University of Texas Southwestern Medical Center., Department of Molecular Biology, Genentech., Department of Radiation Oncology, University of Texas Southwestern Medical Center., Department of Radiology, University of Texas Southwestern Medical Center., Department of Medicine, University of Chicago., Department of Internal Medicine, University of Texas Southwestern Medical Center., University of Texas Southwestern Medical Center., Bioinformatics, UTSW., Department of Statistical Science, Southern Methodist University., Department of Pathology, UT Southwestern Medical Center., UT Southwestern Medical Center., Department of Molecular Biology, Genentech Inc., Department of Molecular Biology, Genentech Research and Early Development.