CD248+ Cancer-Associated Fibroblasts: A Novel Prognostic and Therapeutic Target for Renal Cell Carcinoma

Chao Xu; Keying Zhang; Fa Yang; Xiang Zhou; Shaojie Liu; Yu Li; Shanjin Ma; Xiaolong Zhao; Tong Lu; Shiqi Lu; JiaYu Zhang; Hongji Li; Donghui Han; Weihong Wen; Weijun Qin

doi:10.3389/fonc.2021.773063

CD248⁺ Cancer-Associated Fibroblasts: A Novel Prognostic and Therapeutic Target for Renal Cell Carcinoma

Front Oncol. 2021 Dec 14:11:773063. doi: 10.3389/fonc.2021.773063. eCollection 2021.

Authors

Chao Xu¹, Keying Zhang¹, Fa Yang¹, Xiang Zhou², Shaojie Liu¹, Yu Li¹, Shanjin Ma³, Xiaolong Zhao¹, Tong Lu¹, Shiqi Lu⁴, JiaYu Zhang¹, Hongji Li¹, Donghui Han¹, Weihong Wen⁴, Weijun Qin¹

Affiliations

¹ Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
² Department of Clinical Laboratory, Innovation Port Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, China.
³ Department of Urology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
⁴ Department of Medical Research, Northwestern Polytechnical University, Xi'an, China.

Abstract

Background: The tumor microenvironment (TME) plays an important role in the progression of renal cell carcinoma (RCC). Cancer-associated fibroblasts (CAFs) are considered to constitute a major component of the TME and participate in various tumor-promoting molecular events. We have previously confirmed that CD248 represents a promising biomarker of CAFs, which may provide insight into CAF-based tumor-promoting effects. However, CAF-mediated tumor progression and the potential mechanism of CD248 remain largely unknown in RCC patients.

Methods: Expression profiling and clinical data of RCC patients were obtained from The Cancer Genome Atlas (TCGA) database. An MCP-counter algorithm and Kaplan-Meier survival analysis were performed to explore the prognostic value of CAFs and CD248, respectively. A Pearson correlation coefficient test and Student's t-test were employed to evaluate the relationship between immunosuppressive TME and CD248 or CAFs. Immunohistochemistry and immunofluorescence staining were performed to confirm CD248 expression within CAFs. CD248-specific siRNA was used to investigate the potential function of CD248 in CAF tumor promotion. Differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA), and enrichment analysis were conducted to clarify the function of CD248⁺ CAFs in RCC progression and the associated regulatory mechanism.

Results: CD248 overexpression and CAF infiltration could predict poor RCC prognosis, which may involve the immunosuppressive TME. CD248 may serve as a promising CAFs biomarker and be involved with the tumor-promoting effect of CAFs. Moreover, CD248⁺ CAF infiltration may contribute to RCC progression and an immunosuppressive TME through cell-extracellular matrix (ECM) interactions and metabolism regulation.

Conclusion: CD248⁺ CAFs participate in the regulation of RCC progression and immunosuppressive TME, which may represent a novel prognostic and therapeutic target for RCC.

Keywords: CAFs; CD248; TME; prognostic biomarker; renal cell carcinoma.