Clinical implications of the tumor microenvironment using multiplexed immunohistochemistry in patients with advanced or metastatic renal cell carcinoma treated with nivolumab plus ipilimumab

Purpose: Immune checkpoint inhibitors (ICIs) such as nivolumab and ipilimumab (N/I) are important treatment options for advanced renal cell carcinoma (RCC). The tumor microenvironment (TME) in these ICI-treated patients is largely unknown. Methods: Twenty-four patients treated with N/I between July 2015 and June 2020 were analyzed. Multiplexed immunohistochemistry (mIHC) was conducted to define the TME, including various T cell subsets, B cells, macrophages, and dendritic cells. Results: The median age of the study patients was 61 years (range, 39–80) and 75.0% of these cases were men. The objective response rate with N/I was 50.0%. The densities of the CD8+ cytotoxic T cells (P=0.005), specifically CD137+ CD8+ T cells (P=0.017), Foxp3- CD4+ helper T cells (P=0.003), Foxp3+ CD4+ regulatory T cells (P=0.045), CD68+ CD206- M1 macrophages (P=0.008), and CD68+ CD206+ M2 macrophages (P=0.021) were significantly higher in the treatment responders. At a median follow-up duration of 24.7 months, the median progression-free survival (PFS) was 11.6 months. The high densities (≥median) of Foxp3- CD4+ helper T cells (P=0.016) and CD68+ CD206- M1 macrophages (P=0.008) were significantly associated with better PFS, and the density of CD137+ CD8+ cytotoxic T cells (P=0.079) was marginally associated with better PFS. After multivariate analysis, the higher density of Foxp3- CD4+ helper T cells was independently associated with better PFS (hazard ratio 0.19; P=0.016). Conclusion: The properties and clinical implications of the TME properties in RCC indicate that Foxp3- CD4+ helper T cells, M1 macrophages, and CD137+ CD8+ T cells are potential predictive biomarkers and treatment targets.