Research Paper Volume 11, Issue 17 pp 6999—7020

Prognostic value and immune infiltration of novel signatures in clear cell renal cell carcinoma microenvironment

Wen-Hao Xu 1, 2, *, , Yue Xu 3, *, , Jun Wang 1, 2, *, , Fang-Ning Wan 1, 2, , Hong-Kai Wang 1, 2, , Da-Long Cao 1, 2, , Guo-Hai Shi 1, 2, , Yuan-Yuan Qu 1, 2, , Hai-Liang Zhang 1, 2, , Ding-Wei Ye 1, 2, ,

  • 1 Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
  • 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
  • 3 Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou 215000, P.R. China
* Equal contribution

received: August 8, 2019 ; accepted: August 19, 2019 ; published: September 7, 2019 ;
How to Cite

Copyright © 2019 Xu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Growing evidence has highlighted the immune response as an important feature of carcinogenesis and therapeutic efficacy in clear cell renal cell carcinoma (ccRCC). This study categorized ccRCC cases into high and low score groups based on their immune/stromal scores generated by the ESTIMATE algorithm, and identified an association between these scores and prognosis. Differentially expressed tumor environment (TME)-related genes extracted from common upregulated components in immune and stromal scores were described using functional annotations and protein–protein interaction (PPI) networks. Most PPIs were selected for further prognostic investigation. Many additional previously neglected signatures, including AGPAT9, AQP7, HMGCS2, KLF15, MLXIPL, PPARGC1A, exhibited significant prognostic potential. In addition, multivariate Cox analysis indicated that MIXIPL and PPARGC1A were the most significant prognostic signatures, and were closely related to immune infiltration in TCGA cohort. External prognostic validation of MIXIPL and PPARGC1A was undertaken in 380 ccRCC cases from a real-world cohort. These findings indicate the relevance of monitoring and manipulation of the microenvironment for ccRCC prognosis and precision immunotherapy.


RCC: renal cell carcinoma; ccRCC: clear cell renal cell carcinoma; TME: tumor microenvironment; TCGA: the Cancer Genome Atlas; KIRC: kidney renal clear cell carcinoma; PFS: progression-free survival; OS: overall survival; HR: hazard ratio; CI: confidence interval; GO: Gene Ontology; BP: biological processes; CC: cellular components; MF: molecular functions; KEGG: Kyoto Encyclopedia of Genes and Genomes.