Local blockade of tacrolimus promotes T-cell-mediated tumor regression in systemically immunosuppressed hosts.

Autor:	Veitch M; Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia., Beaumont K; Queensland Emory Drug Discovery Initiative, UniQuest, The University of Queensland, Brisbane, Queensland, Australia., Pouwer R; Queensland Emory Drug Discovery Initiative, UniQuest, The University of Queensland, Brisbane, Queensland, Australia., Chew HY; Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia., Frazer IH; Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia., Soyer HP; Frazer Institute, Dermatology Research Centre, The University of Queensland, Brisbane, Queensland, Australia.; Department of Dermatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia., Campbell S; Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.; Department of Nephrology, Princess Alexandra Hospital, Brisbane, Queensland, Australia., Dymock BW; Queensland Emory Drug Discovery Initiative, UniQuest, The University of Queensland, Brisbane, Queensland, Australia., Harvey A; Queensland Emory Drug Discovery Initiative, UniQuest, The University of Queensland, Brisbane, Queensland, Australia., Cock TA; Queensland Emory Drug Discovery Initiative, UniQuest, The University of Queensland, Brisbane, Queensland, Australia., Wells JW; Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia j.wells3@uq.edu.au.; Frazer Institute, Dermatology Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2023 Sep; Vol. 11 (9).
DOI:	10.1136/jitc-2023-006783
Abstrakt:	Background: Immunosuppressive drugs such as tacrolimus have revolutionized our ability to transplant organs between individuals. Tacrolimus acts systemically to suppress the activity of T-cells within and around transplanted organs. However, tacrolimus also suppresses T-cell function in the skin, contributing to a high incidence of skin cancer and associated mortality and morbidity in solid organ transplant recipients. Here, we aimed to identify a compound capable of re-establishing antitumor T-cell control in the skin despite the presence of tacrolimus. Methods: In this study, we performed time-resolved fluorescence resonance energy transfer to identify molecules capable of antagonizing the interaction between tacrolimus and FKBP12. The capacity of these molecules to rescue mouse and human T-cell function in the presence of tacrolimus was determined in vitro, and the antitumor effect of the lead compound, Q-2361, was assessed in "regressor" models of skin cancer in immunosuppressed mice. Systemic CD8 T-cell depletion and analyses of intratumoral T-cell activation markers and effector molecule production were performed to determine the mechanism of tumor rejection. Pharmacokinetic studies of topically applied Q-2361 were performed to assess skin and systemic drug exposure. Results: Q-2361 potently blocked the interaction between tacrolimus and FKBP12 and reversed the inhibition of the nuclear factor of activated T cells activation by tacrolimus following T-cell receptor engagement in human Jurkat cells. Q-2361 rescued T-cell function in the presence of tacrolimus, rapamycin, and everolimus. Intratumoral injection of Q-2361-induced tumor regression in mice systemically immune suppressed with tacrolimus. Mechanistically, Q-2361 treatment permitted T-cell activation, proliferation, and effector function within tumors. When CD8 T cells were depleted, Q-2361 could not induce tumor regression. A simple solution-based Q-2361 topical formulation achieved high and sustained residence in the skin with negligible drug in the blood. Conclusions: Our findings demonstrate that the local application of Q-2361 permits T-cells to become activated driving tumor rejection in the presence of tacrolimus. The data presented here suggests that topically applied Q-2361 has great potential for the reactivation of T-cells in the skin but not systemically, and therefore represents a promising strategy to prevent or treat skin malignancies in immunosuppressed organ transplant recipients. Competing Interests: Competing interests: The use of Q-2361 as disclosed in this study has been patented (WO2021248189), with JWW, BWD, AH, T-AC, RP, and KB as coinventors. All other authors declare that they have no competing interests. (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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