Noncanonical Hedgehog signaling through Smoothened controls cytotoxic T cell migration in the tumor microenvironment

IF 16.3 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2025-07-11 DOI:10.1126/sciimmunol.adr3127

Chrysa Kapeni, Louise O’Brien, Dilyara Sabirova, Oliver Cast, Valentina Carbonaro, Stephen Clark-Leonard, Anne C. Machel, Flavio Beke, Sarah McDonald, Kate Fife, Maike de la Roche

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引用次数: 0

Abstract

The Hedgehog (Hh) signaling pathway is aberrantly regulated in cancer. Hh inhibitors are successful in treating basal cell carcinoma (BCC) and Sonic Hedgehog–driven medulloblastoma but have largely failed in clinical trials of other solid cancers. We show that Hh inhibitor treatment specifically diminishes CD8 T cell migration into the tumor microenvironment, both in murine cancer models and resected BCCs from patients treated with the Smoothened (Smo) inhibitor vismodegib. Using small-molecule antagonists and genetic knockout models of key Hh signaling components, we demonstrate that the migration defect is mediated exclusively by the signal transducer Smo and not Hh ligands or Gli transcription factors. Smo acts noncanonically as a G protein–coupled receptor to regulate the migration of murine and human CD8 T cells via RhoA. Our data establish a link between Hh inhibition in vivo and the antitumor immune response and provide the basis for improved Hh targeting approaches for patients with cancer.

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非规范Hedgehog信号通过Smoothened控制肿瘤微环境中细胞毒性T细胞的迁移

Hedgehog （Hh）信号通路在癌症中受到异常调控。Hh抑制剂在治疗基底细胞癌（BCC）和Sonic hedgehog驱动的髓母细胞瘤方面取得了成功，但在其他实体癌症的临床试验中大部分失败。我们发现Hh抑制剂治疗特异性地减少了CD8 T细胞向肿瘤微环境的迁移，无论是在小鼠癌症模型中，还是在接受Smoothened （Smo）抑制剂vismodegib治疗的患者切除的bcc中。利用小分子拮抗剂和关键Hh信号组分的基因敲除模型，我们证明了迁移缺陷仅由信号换能器Smo介导，而不是Hh配体或Gli转录因子。Smo作为G蛋白偶联受体通过RhoA调节小鼠和人CD8 T细胞的迁移。我们的数据建立了体内Hh抑制与抗肿瘤免疫应答之间的联系，并为改进Hh靶向治疗癌症患者的方法提供了基础。

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来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.