Complement and coagulation cascades pathway-related signature as a predictor of immunotherapy in metastatic urothelial cancer

Zheng Gong; Yuming He; Xiao Mi; Chengcheng Li; Xiaoran Sun; Guoqiang Wang; Leo Li; Yusheng Han; Chunwei Xu; Wenxian Wang; Shangli Cai; Liang Wang; Zhongyuan Liu

doi:10.18632/aging.205022

Complement and coagulation cascades pathway-related signature as a predictor of immunotherapy in metastatic urothelial cancer

Aging (Albany NY). 2023 Sep 24;15(18):9479-9498. doi: 10.18632/aging.205022. Epub 2023 Sep 24.

Authors

Zheng Gong¹, Yuming He², Xiao Mi², Chengcheng Li², Xiaoran Sun², Guoqiang Wang², Leo Li², Yusheng Han², Chunwei Xu³, Wenxian Wang⁴, Shangli Cai², Liang Wang⁵, Zhongyuan Liu¹

Affiliations

¹ Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110001, China.
² Burning Rock Biotech, Guangzhou 510300, China.
³ Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China.
⁴ Department of Clinical Trial, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou 310022, China.
⁵ The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.

Abstract

Background: Immune checkpoint inhibitors (ICIs) have shown efficacy in patients with metastatic urothelial cancer (mUC), however, only a small subset of patients could benefit from ICIs. Identifying predictive biomarkers of ICIs in patients with mUC is clinical meaningful for patient stratification and administration.

Methods: Clinical and transcriptomic data of mUC patients treated with ICIs from mUC cohort (IMvigor210 study) was utilized to explore the predictive biomarkers. LASSO Cox regression was performed to construct a predictive model. The predictive model was trained and tested in the mUC cohort, and then exploratively tested in clear cell renal cell carcinoma (ccRCC) and melanoma cohorts in which patients also received ICIs regimens.

Results: The differentially expressed genes (DEGs) in complement and coagulation cascades pathway (CCCP) were mainly enriched in non-responders of ICIs in the mUC cohort. A CCCP risk score was constructed based on the DEGs in CCCP. Patients with a low-risk score were more responsive to ICIs and had better overall survival (OS) than those with a high-risk score in the training set (HR, 0.38; 95%CI, 0.27-0.53, P<0.001) and the test set (HR, 0.34; 95%CI, 0.17-0.71, P=0.003). The association between the CCCP risk score and OS remained significant in the multivariable cox regression by adjusting PD-L1 expression and TMB (P<0.05). In addition, there was no difference for OS in the bladder cancer patients without ICIs (TCGA-BLCA cohort, HR, 0.76, 95%CI, 0.49-1.18, P=0.22), suggesting a predictive but not prognostic effect of the risk score. For the exploratory analysis, consistent results were observed that low-risk group showed superior OS in ccRCC cohort (HR, 0.52, 95%CI, 0.37-0.75, P<0.001) and melanoma cohort (HR, 0.27, 95%CI, 0.12-0.62, P=0.001).

Conclusions: Our study showed that the CCCP risk score is an independent biomarker that predicts the efficacy of ICIs in mUC patients. The patients with a low-risk score tend to have a better response to ICIs and a longer life time probably due to the immune-activated TME. Further studies are needed to validate the clinical utility of the seven-gene signature.

Keywords: complement and coagulation cascades; immune checkpoint inhibitor; predictive biomarker; urothelial cancer.