Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation

Abstract

Immune checkpoint inhibitor (ICI) use remains a challenge in patients with solid organ allografts as most would undergo rejection. In a melanoma patient in whom programmed-death 1 (PD-1) blockade resulted in organ rejection and colitis, the addition of the mTOR inhibitor sirolimus resulted in ongoing anti-tumor efficacy while promoting allograft tolerance. Strong granzyme B⁺, interferon (IFN)-γ⁺ CD8⁺ cytotoxic T cell and circulating regulatory T (T_reg) cell responses were noted during allograft rejection, along with significant eosinophilia and elevated serum IL-5 and eotaxin levels. Co-treatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated T_reg cell numbers in the peripheral blood were maintained. Interestingly, numbers of IFN-γ⁺ CD4⁺ T cells and serum IFN-γ levels increased with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy. Thus, our results indicate that sirolimus has the potential to uncouple anti-PD-1 therapy toxicity and efficacy.