Tumour cell expression of interleukin 6 receptor α is associated with response rates in patients treated with sunitinib for metastatic clear cell renal cell carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma, and anti‐angiogenic treatment is currently first line therapy for metastatic ccRCC (mccRCC). Response rates and duration of response show considerable variation, and adverse events have a major influence on patient quality of life. The need for predictive biomarkers to select responders to receptor tyrosine kinase inhibitors upfront is urgent. We investigated the predictive value of immunohistochemical biomarkers associated with angiogenesis and systemic inflammation in mccRCC. Forty‐six patients with metastatic or non‐resectable ccRCC treated with sunitinib were included. Metastatic and/or primary tumour tissue was stained by immunohistochemistry for selected markers related to angiogenesis [vascular endothelial growth factor A (VEGF‐A), VEGF receptor 2 (VEGFR2), platelet‐derived growth factor receptor β (PDGFRβ), and heat shock protein 27 (HSP27)] and immune responses [Interleukin 6 receptor α (IL6Rα), interleukin‐6 (IL6), and jagged1 (JAG1)]. The predictive potential of the candidate markers was assessed by correlations with response rates (RECIST). In addition, progression free survival (PFS) and overall survival (OS) were analysed. Low tumour cell expression of IL6Rα was significantly associated with improved response to sunitinib (Fisher's exact test, p = 0.03), but not with PFS or OS. Median/high expression of IL6Rα showed significant association with median/high expression of VEGF‐A and HSP27. Furthermore, low expression of IL6 was significantly associated with improved PFS, but not OS or response rates. High expression of IL6 was significantly associated with high expression of JAG1, VEGF‐A, VEGFR2, and PDGFRβ. Loss of tumour cell expression of IL6Rα in mccRCC patients treated with sunitinib predicts improved treatment response, and might represent a candidate predictive marker.

Molecules promoting circulating clusters of cancer cells suggest novel therapeutic targets for treatment of metastatic cancers

“…Consistent with the literature, expression of IL6R has strong prognostic value in glioblastoma ( 98 ) and in lung adenocarcinoma ( 99 , 100 ). In contrast, in kidney clear cell carcinoma we found a contradiction between the literature and TCGA data concerning the biomarker potential of IL6R expression: good predictor according to the literature ( 101 , 102 ), and poor predictor according to TCGA data. Thus, the role of IL6R expression in cancer can be considered tissue specific.…”

Identification of IL20RB as a Novel Prognostic and Therapeutic Biomarker in Clear Cell Renal Cell Carcinoma

“…Colony-stimulating factor 1 receptor was reported to be related with unfavorable cancer-specific survival [ 7 ]. Expression of interleukin 6 receptor α was reported to influence response rates, in which low expression of IL6R α comes with a favorable response in patients treated with sunitinib [ 8 ]. In addition, CXCL13 [ 9 ], IL-8, and CXCL1 [ 10 ] were also identified as potential target in ccRCC.…”

PTEN suppresses the inflammation, viability, and motility of AP-AR42J cells by activating the Wnt/β-catenin pathway

“…39 In addition, other inammatory factors such as IL-6, IL-10 and IL-1b are closely related to histrionic necrosis, blood ow congestion and multi-organ dysfunction. 40,41 As demonstrated, high levels of the above inammatory factors in AP model cells could be signicantly decreased by treating with PTEN. In contrast, with post transfection with PTEN-shRNA, an obvious up-regulated expression of IL-6, IL-10, TNF and IL-1b was detectable.…”