Notch activation defines immune-suppressive subsets of ccRCCs with unfavorable benefits from immunotherapy over VEGFR/mTOR inhibitors
Sujun Han,
Yu Xu,
Dong Chen,
Feiya Yang,
Mingshuai Wang,
Qiaoxia Zhou,
Guoqiang Wang,
Leo Li,
Chunwei Xu,
Wenxian Wang,
Shangli Cai,
Nianzeng Xing
Affiliations
Sujun Han
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Yu Xu
Burning Rock Biotech, Guangzhou, Guangdong, China
Dong Chen
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Feiya Yang
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Mingshuai Wang
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Qiaoxia Zhou
Burning Rock Biotech, Guangzhou, Guangdong, China
Guoqiang Wang
Burning Rock Biotech, Guangzhou, Guangdong, China
Leo Li
Burning Rock Biotech, Guangzhou, Guangdong, China
Chunwei Xu
Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
Wenxian Wang
Department of Clinical Trial, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
Shangli Cai
Burning Rock Biotech, Guangzhou, Guangdong, China
Nianzeng Xing
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Urology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China; Corresponding author
Summary: The evolutionarily conserved Notch pathway, involved in cancer stem cell capacity and cancer immunity, may predict the benefit from immune checkpoint inhibitors (ICIs) in clear cell renal cell carcinoma (ccRCC). In the TCGA dataset, mRNA expression of Notch pathway genes identified three clusters with different prognoses and molecular characteristics. Based on the differentially expressed Notch pathway genes between clusters, we constructed the Notch-score, correlated with Notch activation, angiogenesis, PI3K-AKT-mTOR activity, and sensitivities to VEGFR/mTOR inhibitors. A high Notch-score was linked with more “resting”/“anti-inflammatory” rather than “activated”/“pro-inflammatory” tumor-infiltrating immune cells, inactivated immune pathways, and scarce any benefits from ICI-based therapies over VEGFR/mTOR inhibitors in the JAVELIN Renal 101 (avelumab plus axitinib vs. sunitinib) and the CheckMate-009/010/025 trials (nivolumab vs. everolimus). For the Notch-activated ccRCCs, ICIs provide limited advantages and might not be strongly recommended, by which the cost-effectiveness of treatments in ccRCCs may be potentially improved.
