TIM3+ breast cancer cells license immune evasion during micrometastasis outbreak

IF 48.8 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2025-07-10 DOI:10.1016/j.ccell.2025.06.015

Catalina Rozalén, Irene Sangrador, Silvia Avalle, Sandra Blasco-Benito, Panagiota Tzortzi, María Sanz-Flores, José Ángel Palomeque, Pau Torren-Duran, Mariona Dalmau, Helena Brunel, Albert Coll-Manzano, Iván Pérez-Núñez, Tamara Martos, Sonia Servitja, Sandra Pérez-Buira, José Ignacio Chacón, Ángel Guerrero-Zotano, Eduardo Martínez de Dueñas, Yolanda Guillén, Laura Comerma, Toni Celià-Terrassa

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引用次数: 0

Abstract

In metastasis, the dynamics of tumor-immune interactions during micrometastasis remain unclear. Identifying the vulnerabilities of micrometastases before outbreaking into macrometastases can reveal therapeutic opportunities for metastasis. Here, we report a function of T cell immunoglobulin and mucin domain 3 (TIM3) in tumor cells during micrometastasis using breast cancer (BC) metastasis mouse models. TIM3 is highly upregulated in micrometastases, promoting survival, stemness, and immune escape. TIM3⁺ tumor cells are specifically selected during early seeding of micrometastasis. Mechanistically, TIM3 increases β-catenin/interleukin-1β (IL-1β) signaling, leading to stemness and immune-evasion by inducing immunosuppressive γδ T cells and reducing CD8 T cells during micrometastasis. Clinical data confirm increased TIM3⁺ tumor cells in BC metastasis and TIM3⁺ tumor cells as a biomarker of poor outcome in BC patients. (Neo)adjuvant TIM3 blockade reduces the metastatic seeding and incidence in preclinical models. These findings unveil a specific mechanism of micrometastasis immune-evasion and the potential use of TIM3 blockade for subclinical metastasis.

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TIM3+乳腺癌细胞在微转移爆发时允许免疫逃避

在转移中，微转移过程中肿瘤免疫相互作用的动力学尚不清楚。在微转移爆发为大转移之前识别其脆弱性可以揭示转移的治疗机会。在这里，我们报道了T细胞免疫球蛋白和粘蛋白结构域3 （TIM3）在乳腺癌（BC）转移小鼠模型中微转移过程中在肿瘤细胞中的功能。TIM3在微转移中高度上调，促进存活、干性和免疫逃逸。TIM3+肿瘤细胞是在微转移的早期播种阶段特异性选择的。机制上，TIM3增加β-catenin/interleukin-1β (IL-1β)信号，在微转移过程中通过诱导免疫抑制性γδ T细胞和减少CD8 T细胞导致干细胞和免疫逃避。临床数据证实，BC转移中TIM3+肿瘤细胞增多，TIM3+肿瘤细胞是BC患者预后不良的生物标志物。在临床前模型中，（Neo）佐剂TIM3阻断可减少转移的发生和发生率。这些发现揭示了微转移免疫逃避的特定机制，以及TIM3阻断在亚临床转移中的潜在应用。

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.