CXCR3 Expression Is Associated with Advanced Tumor Stage and Grade Influencing Survival after Surgery of Localised Renal Cell Carcinoma

SIMPLE SUMMARY: Localized renal cell carcinoma is primarily treated surgically by resection. Some patients carry criteria for a high risk of tumour recurrence, for which postoperative immunotherapy is approved and currently used. The receptor CXCR3 differentiates anti-tumour T cells, which are known to be significantly increased in patients at high risk of tumor recurrence. The aim of our study therefore was to evaluate occurrence of CXCR3 in tissue samples, to analyse its expression in higher tumor grades and stages and to interpret the results to designate CXCR3 as a potential marker for predicting recurrence in renal cell carcinoma after primary surgical resection. ABSTRACT: Background: Surgery is the standard treatment in localized renal cell carcinoma (RCC). Pembrolizumab is now approved for adjuvant therapy in high-risk patients. However, inhomogeneity of studies gives ambiguity which patient benefit most from adjuvant therapy. A high infiltration of CD8(+) T cells is known to be linked with poor prognosis in RCC. CXCR3 is a key player of CD8(+) T cell differentiation and infiltration. We aimed to evaluate CXCR3 as a potential marker for predicting recurrence. Methods: CXCR3 and immune cell subsets (CD4, CD8, CD68 and FoXP3) were measured on RCC samples by multiplex immunofluorescence (mIF) staining. Cellular localization of CXCR3 was evaluated using single-cell RNA analysis on a publicly available dataset. Results: Tumor samples of 42 RCC patients were analyzed, from which 59.5% were classified as clear-cell RCC and of which 20 had recurrence. Single-cell RNA analysis revealed that CXCR3 was predominantly expressed in intratumoral T cells and dendritic cells. CXCR3 expression was higher in advanced tumors stages (p = 0.0044) and grade (p = 0.0518), correlating significantly with a higher CD8(+) T cell expression (p < 0.001). Patients with CXCR3(high) RCCs had also a significant shorter RFS compared to CXCR3(low) (median: 78 vs. 147 months, p = 0.0213). In addition, also tumor stage pT3/4 (p < 0.0001) as well as grade G3/4 (p = 0.0008) negatively influenced RFS. Conclusion: CXCR3(high) cell density was associated with high T cell infiltration and advanced tumor stage, worsening RFS in surgically resected RCC patients. Beside its prognostic value, CXCR3 might be a predictive biomarker to guide therapy decision for adjuvant therapy in localized RCC.