UBR5 Serves As a Tumor Suppressor in Clear Cell Renal Cell Carcinoma and Integrating Intratumoral UBR5 with Tumor Associated Macrophages Achieves Better Prognostic Accuracy

Abstract

Background: Interaction between tumors and tumor-infiltrating immune cells (TIICs) has been reported to facilitate the progression of clear cell renal cell carcinoma (ccRCC), but whether combining intra-tumoral markers and TIICs better predicts patients' prognosis remains unknown. This study mainly determined the prognostic value of a novel tumor-suppressor UBR5 in ccRCC patients by combining with tumor-associated macrophages (TAMs). Methods: Immunohistochemistry (IHC) and statistical analyses were performed to examine the prognostic value of UBR5 and TIICs in two independent cohorts of ccRCC patients. In vitro functional assays, in vivo tumor xenograft experiments, and a co-culture system were used to examine the biological role of UBR5 and its interaction with TAMs in ccRCC. Findings: UBR5 was commonly down-regulated in human ccRCC and negatively associated with disease progression and poor prognosis of ccRCC patients. In addition, UBR5 expression was inversely correlated with infiltration of TAMs in ccRCC, and combining expressions of UBR5 and TAMs better predicted ccRCC patients' prognosis. Even after multivariable adjustment, UBR5 and TAMs appeared to be independent risk factors respectively. By time-dependent c-index analysis, the incorporation of both UBR5 and TAMs into the clinical indicators TNM stage or SSIGN score exhibited higher c-index value than anyone of them alone. Furthermore, above results were confirmed in the randomized training, validation, and combined cohorts. Moreover, UBR5 inhibited proliferation, induced apoptosis, suppressed invasion, migration and in vivo tumor growth of ccRCC cells. In addition, intra-tumoral UBR5 inhibited the recruitment and activation of TAMs, which alleviated the increased malignant characteristics of ccRCC cells induced by TAMs. Interpretation: UBR5 serves as a tumor-suppressor in ccRCC and inhibits ccRCC-TAMs interaction. Moreover, integrating intra-tumoral UBR5 expression and TAMs with the current clinical parameters achieves better prognostic accuracy. Funding Statement: This work was supported by The Top-level Clinical Discipline Project of Shanghai Pudong (PWYgf2018-03), National Natural Science Foundation of China (No. 81772747, 81773154, 81974391), the Program of Shanghai Academic/Technology Research Leader (No. 19XD1405100), the Shanghai Rising Stars of Medical Youth Development Program: Outstanding Youth Medical Talents (Xin-gang Cui), Meng Chao Talent Training Program--Cultivation of Leading Talents Reserve (Xin-gang Cui), and the Shanghai Medical Guidance (Chinese and Western Medicine) Science and Technology Support Project (No. 17411960200). Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: All experiments were approved by the institutional ethical review boards from all hospitals, and all written informed consents were obtained from the ccRCC patients.