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- Title
Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation.
- Authors
Esfahani, Khashayar; Al-Aubodah, Tho-Alfakar; Thebault, Pamela; Lapointe, Réjean; Hudson, Marie; Johnson, Nathalie A.; Baran, Dana; Bhulaiga, Najwa; Takano, Tomoko; Cailhier, Jean-François; Piccirillo, Ciriaco A.; Miller, Wilson H.
- 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. The use of immune checkpoint inhibitors (ICI) in cancer patients with solid organ allografts is hampered due to potential organ rejection. Here, the authors present a case report of a patient with kidney allograft and show that treatment with the mTOR inhibitor sirolimus preserves peripheral tolerance and anti-tumour efficacy of ICI therapy.
- Subjects
CYTOTOXIC T cells; EOSINOPHILIA; PROGRAMMED cell death 1 receptors; SUPPRESSOR cells; BRAF genes; T cells; RAPAMYCIN; IMMUNE checkpoint inhibitors
- Publication
Nature Communications, 2019, Vol 10, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-12628-1