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

Khashayar Esfahani,Réjean Lapointe,Tomoko Takano,Pamela Thebault,Marie Hudson,Jean-François Cailhier,Wilson H Miller,Najwa Bhulaiga,Nathalie A Johnson,Dana Baran,Tho-Alfakar Al-Aubodah,Ciriaco A Piccirillo

doi:10.1038/s41467-019-12628-1

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 (Treg) 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 Treg 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.

Highlights

Immune checkpoint inhibitor (ICI) use remains a challenge in patients with solid organ allografts as most would undergo rejection
While programmeddeath 1 (PD-1) inhibitors lead to widespread T cell activation, the mammalian target of rapamycin, a central integrator of the metabolic and immune signals associated with T cell activation, is emerging as a critical driver and modulator of T cell differentiation, function, and homeostasis[6]
We present a detailed immunophenotyping of peripheral blood from a patient who underwent kidney allograft rejection and some immune-related adverse events (irAEs) while on PD-1 blockade and was subsequently controlled using ICI-mTOR inhibition (mTORi) combination therapy

Summary

Introduction

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 programmeddeath 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. Immune checkpoint inhibitors (ICIs) are among the most promising approaches to fighting cancer[1] Immune checkpoints, such as the programmed-death 1 (PD-1) or the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), are physiological immunoinhibitory and regulatory components of the immune system that counteract immune activation to maintain immune homeostasis, promote self-tolerance, and protect against autoimmunity. ICI-mTORi combination therapy maintained elevated frequencies of CD4+ and CD8+ T cells producing the pro-inflammatory cytokine interferon (IFN)-γ in peripheral blood, as well as increased numbers of regulatory T (TREG) cells, an adaptive immune subset critical for allograft tolerance and tissue homeostasis. Our data indicate that the inclusion of mTORi to PD-1 inhibition could change the immune landscape in favor of allograft preservation without compromising anti-tumor efficacy

Methods

Results

Conclusion