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

© 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..

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.

Medienart:	E-Artikel

Erscheinungsjahr:	2023
Erschienen:	2023

Enthalten in:	Zur Gesamtaufnahme - volume:11
Enthalten in:	Journal for immunotherapy of cancer - 11(2023), 9 vom: 01. Sept.

Sprache:	Englisch

Beteiligte Personen:	Veitch, Margaret [VerfasserIn] Beaumont, Kimberly [VerfasserIn] Pouwer, Rebecca [VerfasserIn] Chew, Hui Yi [VerfasserIn] Frazer, Ian H [VerfasserIn] Soyer, H Peter [VerfasserIn] Campbell, Scott [VerfasserIn] Dymock, Brian W [VerfasserIn] Harvey, Andrew [VerfasserIn] Cock, Terrie-Anne [VerfasserIn] Wells, James W [VerfasserIn]

Links:	Volltext

Themen:	CD4-Positive T-Lymphocytes CD8-Positive T-Lymphocytes EC 5.2.1.- Immunosuppressive Agents Journal Article Research Support, Non-U.S. Gov't Skin Neoplasms Tacrolimus Tacrolimus Binding Protein 1A Therapies, Investigational Transplantation Immunology WM0HAQ4WNM

Anmerkungen:	Date Completed 11.09.2023 Date Revised 15.09.2023 published: Print Citation Status MEDLINE

doi:	10.1136/jitc-2023-006783

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	NLM361765215