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

Khashayar Esfahani, Tho-Alfakar Al-Aubodah, Pamela Thebault, Réjean Lapointe, Marie Hudson, Nathalie A. Johnson, Dana Baran, Najwa Bhulaiga, Tomoko Takano, Jean-François Cailhier, Ciriaco A. Piccirillo () and Wilson H. Miller ()
Additional contact information
Khashayar Esfahani: McGill University
Tho-Alfakar Al-Aubodah: Centre of Excellence in Translational Immunology (CETI)
Pamela Thebault: University of Montréal Hospital Research Centre
Réjean Lapointe: University of Montréal Hospital Research Centre
Marie Hudson: Centre of Excellence in Translational Immunology (CETI)
Nathalie A. Johnson: Centre of Excellence in Translational Immunology (CETI)
Dana Baran: McGill University
Najwa Bhulaiga: McGill University
Tomoko Takano: Centre of Excellence in Translational Immunology (CETI)
Jean-François Cailhier: University of Montréal Hospital Research Centre
Ciriaco A. Piccirillo: Centre of Excellence in Translational Immunology (CETI)
Wilson H. Miller: McGill University

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12628-1

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