A New Signature That Predicts Progression-Free Survival of Clear Cell Renal Cell Carcinoma with Anti-PD-1 Therapy

Author:

Lin Jingwei1ORCID,Cai Yingxin1,Ma Yuxiang1,Pan Jinyou1,Wang Zuomin1,Zhang Jianpeng1,Liu Yangzhou1,Zhao Zhigang1

Affiliation:

1. Department of Urology & Andrology, Minimally Invasive Surgery Center, Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510230, China

Abstract

Immunotherapy has greatly improved the survival time and quality of life of patients with renal cell carcinoma, but the benefits are limited to a small portion of patients. There are too few new biomarkers that can be used to identify molecular subtypes of renal clear cell carcinoma and predict survival time with anti-PD-1 treatment. Single-cell RNA data of clear cell renal cell carcinoma (ccRCC) treated with anti-PD-1 were obtained from public databases, then 27,707 high-quality CD4 + T and CD8 + T cells were obtained for subsequent analysis. Firstly, genes set variation analysis and CellChat algorithm were used to explore potential molecular pathway differences and intercellular communication between the responder and non-responder groups. Additionally, differentially expressed genes (DEGs) between the responder and non-responder groups were obtained using the “edgeR” package, and ccRCC samples from TCGA-KIRC (n = 533) and ICGA-KIRC (n = 91) were analyzed by the unsupervised clustering algorithm to recognize molecular subtypes with different immune characteristics. Finally, using univariate Cox analysis, least absolute shrinkage and selection operator (Lasso) regression, and multivariate Cox regression, the prognosis model of immunotherapy was established and verified to predict the progression-free survival of ccRCC patients treated with anti-PD-1. At the single cell level, there are different signal pathways and cell communication between the immunotherapy responder and non-responder groups. In addition, our research also confirms that the expression level of PDCD1/PD-1 is not an effective marker for predicting the response to immune checkpoint inhibitors (ICIs). The new prognostic immune signature (PIS) enabled the classification of ccRCC patients with anti-PD-1 therapy into high- and low-risk groups, and the progression-free survival times (PFS) and immunotherapy responses were significantly different between these two groups. In the training group, the area under the ROC curve (AUC) for predicting 1-, 2- and 3-year progression-free survival was 0.940 (95% CI: 0.894–0.985), 0.981 (95% CI: 0.960–1.000), and 0.969 (95% CI: 0.937–1.000), respectively. Validation sets confirm the robustness of the signature. This study revealed the heterogeneity between the anti-PD-1 responder and non-responder groups from different angles and established a robust PIS to predict the progression-free survival of ccRCC patients receiving immune checkpoint inhibitors.

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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