Abstract
Costimulatory molecules have been proven to enhance antitumor immune responses, but their roles in clear cell renal cell carcinoma (ccRCC) remain unexplored. In this study, we aimed to explore the gene expression profiles of costimulatory molecule genes in ccRCC and construct a prognostic signature to improve treatment decision-making and clinical outcomes. We performed the first comprehensive analysis of costimulatory molecules in patients with ccRCC and identified 13 costimulatory molecule genes with prognostic values and diagnostic values. Consensus clustering analysis based on these 13 costimulatory molecular genes showed different distribution patterns and prognostic differences for the two clusters identified. Then, a costimulatory molecule-related signature was constructed based on these 13 costimulatory molecular genes, and validated in an external dataset, showing good performance for predicting a patient’s prognosis. The signature was an independent risk factor for ccRCC patients and was significantly correlated with patients’ clinical factors, which could be used as a complement for clinical factors. In addition, the signature was associated with the tumor immune microenvironment and the response to immunotherapy. Patients identified as high-risk based on our signature exhibited a high mutation frequency, a high level of immune cell infiltration, and an immunosuppressive microenvironment. High-risk patients tended to have high cytolytic activity scores and immunophenoscore of CTLA4 and PD1/PD-L1/PD-L2 blocker than low-risk patients, suggesting these patients may be more suitable for immunotherapy. Therefore, our signature could provide clinicians with prognosis predictions and help guide treatment for ccRCC patients.
Highlights
Renal cell carcinoma (RCC) is one of the most common malignancies of the urinary system, estimating that 73,750 new cases and 14,830 deaths will occur in the United States in 2020 [1]
CcRCC has shown durable responses to Immune checkpoint inhibition (ICI) therapies, and nivolumab has been approved as a second-line treatment for metastatic RCC [15]
A large part of Clear cell renal cell carcinoma (ccRCC) patients does not respond to ICI therapies
Summary
Renal cell carcinoma (RCC) is one of the most common malignancies of the urinary system, estimating that 73,750 new cases and 14,830 deaths will occur in the United States in 2020 [1]. Clear cell renal cell carcinoma (ccRCC), the most common histological subtype, is the leading cause of death of RCC patients [2]. CcRCC is chemo- and radio-resistant neoplasia and alternative treatment options have been limited [6]. In recent years, targeted therapies and immunotherapies have further improved the prognosis of ccRCC. Only a small percentage of ccRCC patients can benefit from these therapies [7, 8]. Identifications of new biomarkers to predict patients’ survival and response to targeted therapies and immunotherapies are urgently needed
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