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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 &amp;gt;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.<\/jats:p>\n                  <jats:p>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\u201355. \u00a92018 AACR.<\/jats:p>\n                  <jats:p>This article is highlighted in the In This Issue feature, p. 1047<\/jats:p>","DOI":"10.1158\/2159-8290.cd-17-1246","type":"journal-article","created":{"date-parts":[[2018,6,8]],"date-time":"2018-06-08T14:55:12Z","timestamp":1528469712000},"page":"1142-1155","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":157,"title":["An Empirical Approach Leveraging Tumorgrafts to Dissect the Tumor Microenvironment in Renal Cell Carcinoma Identifies Missing Link to Prognostic Inflammatory Factors"],"prefix":"10.1158","volume":"8","author":[{"given":"Tao","family":"Wang","sequence":"first","affiliation":[{"name":"1Quantitative Biomedical Research Center, Department of Clinical Sciences, The University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"2Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"3Center for the Genetics of Host Defense, The University of Texas Southwestern Medical Center, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Lu","sequence":"additional","affiliation":[{"name":"1Quantitative Biomedical Research Center, Department of Clinical Sciences, The University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"4Bioinformatics Core Facility, The University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Payal","family":"Kapur","sequence":"additional","affiliation":[{"name":"2Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"5Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bijay 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