类似他克莫司的免疫抑制药物为器官移植之间的领域做出了革命性的贡献。他克莫司通过全身作用来抑制器官移植区域内外的T细胞活性。然而，他克莫司也会抑制皮肤中的T细胞功能，导致固体器官移植受体皮肤癌的发生率高，相关的死亡率和发病率也较高。本研究旨在寻找一种能够在存在他克莫司的情况下重新建立皮肤抗肿瘤T细胞控制的化合物。 在本研究中，我们进行了时间分辨荧光共振能量转移实验，以鉴定能够拮抗他克莫司和FKBP12之间相互作用的分子。通过体外实验确定了这些分子在存在他克莫司的情况下是否能够恢复小鼠和人类T细胞的功能，并评估了引导化合物Q-2361在免疫抑制小鼠皮肤癌“退化”模型中的抗肿瘤效果。采用全身CD8 T细胞去除和肿瘤内T细胞活化标记物和效应分子生成的分析来确定肿瘤排斥的机制。通过药代动力学研究评估了局部应用Q-2361的皮肤和全身药物暴露情况。 Q-2361有效地阻断了他克莫司和FKBP12之间的相互作用，并逆转了他克莫司对人源Jurkat细胞中细胞内活化的核因子的抑制，该细胞在T细胞受体激活后被诱发。Q-2361在他克莫司、雷帕霉素和依维莫司存在下恢复了T细胞的功能。Q-2361的肿瘤内注射在免疫抑制小鼠体内引起了肿瘤的退化。在机制上，Q-2361治疗促使肿瘤内的T细胞激活、增殖和效应功能。当CD8 T细胞被去除时，Q-2361不能引起肿瘤退化。一种简单的基于溶液的Q-2361局部制剂在皮肤中具有高度和持久的皮肤残留量，而在血液中几乎没有药物。 我们的发现表明，局部应用Q-2361能够在存在他克莫司的情况下激活T细胞，促进肿瘤排斥。本研究所呈现的数据表明，局部应用Q-2361在预防或治疗免疫抑制器官移植受体皮肤恶性肿瘤方面具有巨大的潜力，但其在全身方面并没有相似的效果，因此代表了一个有希望的策略。 © 作者（或其雇主）2023。使用权由CC BY-NC许可。不得用于商业用途。详见权利和权限。由BMJ出版发表。

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.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.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.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.© 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.