Azin Marjan, Ngo Kenneth H, Hojanazarova Jennet, Demehri Shadmehr
Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Center for Cancer Immunology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
JID Innov. 2023 Aug 12;3(6):100221. doi: 10.1016/j.xjidi.2023.100221. eCollection 2023 Nov.
Nonkeratinocyte cutaneous malignancies, including breast cancer cutaneous metastasis and melanoma in situ, are often poor surgical candidates. Imiquimod (IMQ), a toll-like receptor 7 agonist that activates innate immunity in the skin, is used to treat these cutaneous malignancies. However, IMQ's modest effect on the activation of adaptive immunity limits its efficacy as a monotherapy. In this study, we demonstrate that topical TSLP cytokine inducers-calcipotriol and retinoic acid-synergize with IMQ to activate CD4 T-cell immunity against nonkeratinocyte cutaneous malignancies. Topical calcipotriol plus IMQ treatment reduced breast tumor growth compared with calcipotriol or IMQ alone ( < 0.0001). Calcipotriol plus IMQ-mediated tumor suppression was associated with significant infiltration of CD4 effector T cells in the tumor microenvironment. Notably, topical calcipotriol plus IMQ immunotherapy enabled immune checkpoint blockade therapy to effectively control immunologically cold breast tumors, which was associated with induction of CD4 T-cell immunity. Topical treatment with calcipotriol plus IMQ and retinoic acid plus IMQ also blocked subcutaneous melanoma growth. These findings highlight the synergistic effect of topical TSLP induction in combination with innate immune cell activation as an effective immunotherapy for malignancies affecting the skin.
非角质形成细胞皮肤恶性肿瘤，包括乳腺癌皮肤转移瘤和原位黑色素瘤，通常不是手术的理想候选对象。咪喹莫特（IMQ）是一种 toll 样受体 7 激动剂，可激活皮肤中的固有免疫，用于治疗这些皮肤恶性肿瘤。然而，IMQ 对适应性免疫激活的作用有限，限制了其作为单一疗法的疗效。在本研究中，我们证明局部使用胸腺基质淋巴细胞生成素（TSLP）细胞因子诱导剂——骨化三醇和视黄酸——与 IMQ 协同作用，激活针对非角质形成细胞皮肤恶性肿瘤的 CD4 T 细胞免疫。与单独使用骨化三醇或 IMQ 相比，局部使用骨化三醇加 IMQ 治疗可减少乳腺肿瘤生长（<0.0001）。骨化三醇加 IMQ 介导的肿瘤抑制与肿瘤微环境中 CD4 效应 T 细胞的显著浸润有关。值得注意的是，局部使用骨化三醇加 IMQ 免疫疗法使免疫检查点阻断疗法能够有效控制免疫冷性乳腺肿瘤，这与 CD4 T 细胞免疫的诱导有关。局部使用骨化三醇加 IMQ 和视黄酸加 IMQ 治疗也能阻止皮下黑色素瘤的生长。这些发现突出了局部诱导 TSLP 与激活固有免疫细胞相结合作为治疗影响皮肤的恶性肿瘤的有效免疫疗法的协同作用。
