Nivolumab Reduces PD1 Expression and Alters Density and Proliferation of Tumor Infiltrating Immune Cells in a Tissue Slice Culture Model of Renal Cell Carcinoma

SIMPLE SUMMARY: Immune checkpoint inhibitors (ICIs) have become a first-choice therapy option in the treatment of clear cell renal cell carcinoma (ccRCC). A predictive biomarker is urgently needed since not all patients respond and adverse events occur. Therefore, an ex vivo tissue slice culture (TSC) model was tested to investigate the effects of nivolumab on tumor infiltrating immune cells (TIIC). A decrease in programmed death receptor 1 expression, as well as effects on density and proliferation of TIIC, were observed. Thus, the TSC model could serve as a test platform for response prediction to ICIs. ABSTRACT: Background: In the treatment of clear cell renal cell carcinoma (ccRCC), nivolumab is an established component of the first-line therapy with a favorable impact on progression free survival and overall survival. However, treatment-related adverse effects occur and, to date, there is no approved predictive biomarker for patient stratification. Thus, the aim of this study was to establish an ex vivo tissue slice culture model of ccRCC and to elucidate the impact of nivolumab on tumor infiltrating immune cells. Methods: Fresh tumor tissue of ccRCC was treated with the immune checkpoint inhibitor nivolumab using ex vivo tissue slice culture (TSC). After cultivation, tissue slices were formalin-fixed, immunohistochemically stained and analyzed via digital image analysis. Results: The TSC model was shown to be suitable for ex vivo pharmacological experiments on intratumoral immune cells in ccRCC. PD1 expression on tumor infiltrating immune cells was dose-dependently reduced after nivolumab treatment (p < 0.01), whereas density and proliferation of tumor infiltrating T-cells and cytotoxic T-cells were inter-individually altered with a remarkable variability. Tumor cell proliferation was not affected by nivolumab. Conclusions: This study could demonstrate nivolumab-dependent effects on PD1 expression and tumor infiltrating T-cells in TSC of ccRCC. This is in line with results from other scientific studies about changes in immune cell proliferation in peripheral blood in response to nivolumab. Thus, TSC of ccRCC could be a further step to personalized medicine in terms of testing the response of individual patients to nivolumab.