Pathological findings of immunotherapy-induced nephrotoxicity in a humanized immune system mouse model

Abstract

While immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, they can elicit organ-related immune-related adverse events (irAEs) such as kidney injury. Here, our study evaluated the ability of a humanized immune system (HIS) tumor-bearing mouse model to investigate ICI-mediated kidney injury. Non-humanized (BRGS) and humanized (HIS-BRGS) mice were implanted with human breast cancer cells and treated with either nivolumab (anti-PD-1) or a combination of nivolumab and ipilimumab (anti-CTLA-4) for four weeks. Histopathological analysis revealed that HIS-BRGS mice treated with ICIs exhibited significant interstitial nephritis and vasculitis/periarteritis, consistent with kidney phenotypes observed in patients. Combination therapy resulted in more extensive kidney pathology than nivolumab alone and exhibited an accumulation of T helper cells in the affected areas. Importantly, our results suggest that HIS-BRGS mice can effectively recapitulate features of ICI-induced kidney injury observed in patients and can be used to study mechanisms and prevention strategies to limit irAEs.

Keywords: acute kidney injury; animal model; cancer; lymphocytes; nephrotoxicity; renal pathology.