TY - JOUR
T1 - An empirical approach leveraging tumorgrafts to dissect the tumor microenvironment in renal cell carcinoma identifies missing link to prognostic inflammatory factors
AU - Wang, Tao
AU - Lu, Rong
AU - Kapur, Payal
AU - Jaiswal, Bijay S.
AU - Hannan, Raquibul
AU - Zhang, Ze
AU - Pedrosa, Ivan
AU - Luke, Jason J.
AU - Zhang, He
AU - Goldstein, Leonard D.
AU - Yousuf, Qurratulain
AU - Gu, Yi Feng
AU - McKenzie, Tiffani
AU - Joyce, Allison
AU - Kim, Min S.
AU - Wang, Xinlei
AU - Luo, Danni
AU - Onabolu, Oreoluwa
AU - Stevens, Christina
AU - Xie, Zhiqun
AU - Chen, Mingyi
AU - Filatenkov, Alexander
AU - Torrealba, Jose
AU - Luo, Xin
AU - Guo, Wenbin
AU - He, Jingxuan
AU - Stawiski, Eric
AU - Modrusan, Zora
AU - Durinck, Steffen
AU - Seshagiri, Somasekar
AU - Brugarolas, James
N1 - Funding Information:
We acknowledge the UT Southwestern Tissue Shared Resource for collecting patient tissue samples. We acknowledge the UTSW Flow Cytometry Core for providing help with the single-cell sequencing experiments. We acknowledge the UTSW Kidney Spore Histology core for providing help with all IHC experiments. We acknowledge Eva Moresco and Jessie Norris for their helpful comments on the writing of this article. This study was supported by the NIH (R03 ES026397-01 to T. Wang; R01 GM110050-01A1 to M. Chen; R01 CA175754 to J. Brugarolas; SPORE 1P50CA19651601 to P. Kapur, J. Brugarolas, T. Wang, and I. Pedrosa; R01 CA154475 to I. Pedrosa; CCSG 5P30CA142543 to T. Wang), Center for Translational Medicine of UT Southwestern (SPG2016-018 to T. Wang), Cancer Prevention and Research Institute of Texas (CPRITRP150596 to M.S. Kim, Z. Zhang, R. Lu, D. Luo), and American Cancer Society (RSG-16-001-01-CCE to R. Hannan). This work was also partially supported by fundraising efforts orchestrated by the KCP Patient Council and the Kidney Cancer Coalition. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Funding Information:
We acknowledge the UT Southwestern Tissue Shared Resource for collecting patient tissue samples. We acknowledge the UTSW Flow Cytometry Core for providing help with the single-cell sequencing experiments. We acknowledge the UTSW Kidney Spore Histology core for providing help with all IHC experiments. We acknowledge Eva Moresco and Jessie Norris for their helpful comments on the writing of this article. This study was supported by the NIH (R03 ES026397-01 to T. Wang; R01 GM110050-01A1 to M. Chen; R01 CA175754 to J. Brugarolas; SPORE 1P50CA19651601 to P. Kapur, J. Brugarolas, T. Wang, and I. Pedrosa; R01 CA154475 to I. Pedrosa; CCSG 5P30CA142543 to T. Wang), Center for Translational Medicine of UT Southwestern (SPG2016-018 to T. Wang), Cancer Prevention and Research Institute of Texas (CPRITRP150596 to M.S. Kim, Z. Zhang, R. Lu, D. Luo), and American Cancer Society (RSG-16-001-01-CCE to R. Hannan). This work was also partially supported by fundraising efforts orchestrated by the KCP Patient Council and the Kidney Cancer Coalition.
Publisher Copyright:
©2018 American Association for Cancer Research.
PY - 2018/9
Y1 - 2018/9
N2 - 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.
AB - 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.
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U2 - 10.1158/2159-8290.CD-17-1246
DO - 10.1158/2159-8290.CD-17-1246
M3 - Article
C2 - 29884728
AN - SCOPUS:85053203753
SN - 2159-8274
VL - 8
SP - 1142
EP - 1155
JO - Cancer Discovery
JF - Cancer Discovery
IS - 9
ER -