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

Abstract

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.