分泌白细胞介素-17A的γδ T细胞通过CX3CR1巨噬细胞促进HRHER2乳腺癌对细胞周期蛋白依赖性激酶4/细胞周期蛋白依赖性激酶6抑制剂的抗性。
IL-17A-secreting γδ T cells promote resistance to CDK4/CDK6 inhibitors in HRHER2 breast cancer via CX3CR1 macrophages.
作者信息
Petroni Giulia, Galassi Claudia, Gouin Kenneth H, Chen Hsiang-Han, Buqué Aitziber, Bloy Norma, Yamazaki Takahiro, Sato Ai, Beltrán-Visiedo Manuel, Campia Ginevra, Jiménez-Cortegana Carlos, Shah Aagam, Kirchmair Alexander, Massa Chiara, Wickenhauser Claudia, de Andrea Carlos Eduardo, Navarro-Rubio Belén, Serrano-Mendioroz Irantzu, Navarro Manzano Esther, Satty Alexandra M, Rippon Brady, Finotello Francesca, Trajanoski Zlatko, Zhou Xi Kathy, Scandura Joseph M, García-Martínez Elena, Ayala de la Peña Francisco, Rodríguez-Ruiz María Esperanza, Seliger Barbara, Sánchez-Margalet Víctor, de la Cruz-Merino Luis, Basho Reva K, Shiao Stephen L, McArthur Heather L, Formenti Silvia C, Knott Simon R V, Galluzzi Lorenzo
机构信息
Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
出版信息
Nat Cancer. 2025 Jul 7. doi: 10.1038/s43018-025-01007-z.
Resistance to cyclin-dependent kinase 4/6 (CDK4/CDK6) inhibitors leads to treatment failure and disease progression in women with hormone receptorHER2 (HRHER2) breast cancer (BC). We delineated a hypoxia-sensitive, CCL2-dependent pathway recruiting interleukin-17A (IL-17A)-secreting γδ T cells to mouse HRHER2 BCs following CDK4/CDK6 inhibition, resulting in repolarization of tumor-associated macrophages (TAMs) toward an immunosuppressive CX3CR1 phenotype associated with resistance. Increased IL-17A signaling and intratumoral γδ T cell abundance positively correlated with advanced grade and/or reduced survival in two cohorts of individuals with HRHER2 BC. Circulating γδ T cells and plasma CCL2 levels negatively correlated with progression in an independent series of individuals with HRHER2 BC receiving CDK4/CDK6 inhibitors. Intratumoral γδ T cells were increased in post- versus pretreatment biopsies from individuals with HRHER2 BC relapsing on CDK4/CDK6 inhibitors. CX3CR1 TAMs had negative prognostic impact in women with HRHER2 BC receiving neoadjuvant PD-1 blockage and radiotherapy. Thus, γδ T cells and CX3XR1 TAMs may favor resistance to CDK4/CDK6 inhibitors in individuals with HRHER2 BC.
对细胞周期蛋白依赖性激酶4/6（CDK4/CDK6）抑制剂产生耐药会导致激素受体阳性人表皮生长因子受体2阴性（HR⁺HER2⁻）乳腺癌（BC）女性患者的治疗失败和疾病进展。我们描绘了一条缺氧敏感、CC趋化因子配体2（CCL2）依赖性途径，该途径在CDK4/CDK6抑制后将分泌白细胞介素-17A（IL-17A）的γδT细胞募集到小鼠HR⁺HER2⁻BC中，导致肿瘤相关巨噬细胞（TAM）向与耐药相关的免疫抑制CX3CR1表型重新极化。在两组HR⁺HER2⁻BC患者中，IL-17A信号增加和肿瘤内γδT细胞丰度与高级别和/或生存率降低呈正相关。在接受CDK4/CDK6抑制剂治疗的HR⁺HER2⁻BC独立患者系列中，循环γδT细胞和血浆CCL2水平与疾病进展呈负相关。在因CDK4/CDK6抑制剂复发的HR⁺HER2⁻BC患者的治疗后与治疗前活检中，肿瘤内γδT细胞增加。CX3CR1⁺TAM对接受新辅助程序性死亡蛋白1（PD-1）阻断和放疗的HR⁺HER2⁻BC女性患者具有负面预后影响。因此，γδT细胞和CX3XR1⁺TAM可能有利于HR⁺HER2⁻BC患者对CDK4/CDK6抑制剂产生耐药。
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