肿瘤细胞治疗研究
英文原题：NK cell-triggered CCL5/IFNγ-CXCL9/10 axis underlies the clinical efficacy of neoadjuvant anti-HER2 antibodies in breast cancer.
NK cell-triggered CCL5/IFNγ-CXCL9/10 axis underlies the clinical efficacy of neoadjuvant anti-HER2 antibodies in breast cancer.
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本研究发现，特化的 NK 细胞亚群是影响抗 HER2 抗体临床疗效的 IFN- 来源。研究还揭示了血清 CCL5/CXCL9 作为生物标志物的潜力，可用于识别 NK 细胞富集肿瘤且对基于抗 HER2 抗体的新辅助治疗反应良好的患者。
抗HER2抗体新辅助治疗反应的变异性促使人们进行个性化临床管理并开发创新治疗策略。在原发性HER2阳性乳腺癌患者中，肿瘤浸润性自然杀伤（TI-NK）细胞可独立于临床病理因素预测HER2靶向抗体的疗效。理解这一关联背后的机制将有助于优化患者分层，并为与免疫治疗的联合策略提供理论依据。
我们试图通过微阵列分析揭示与NK细胞荒漠型肿瘤相比，NK细胞浸润型肿瘤中富集的生物学过程。研究结果在临床试验来源的转录组数据中得到验证。采用体外和体内临床前模型进行机制研究。研究结果在乳腺癌患者的临床样本（肿瘤和血清）中进行分析。
NK 细胞浸润的肿瘤富含 CCL5/IFNG-CXCL9/10 转录本。在多因素 logistic 回归分析中，IFNG 水平是 TI-NK 细胞与曲妥珠单抗新辅助治疗病理完全缓解之间关联的基础。在机制上，CD16+ NK 细胞产生 IFN- 触发癌细胞分泌 CXCL9/10。这种效应与在人源化体内模型中肿瘤生长控制以及 CD16 向 CD16-CD103+ NK 细胞的转化相关。在人乳腺肿瘤中，CD16 和 CD103 标志物识别出能够产生 CCL5 和 IFN- 的谱系相关 NK 细胞亚群，其与组织驻留 CD8+ T 细胞相关。最后，血清 CCL5/CXCL9 水平的早期升高识别出 NK 细胞丰富的肿瘤患者，这些患者对基于抗 HER2 抗体的新辅助治疗表现出良好的应答。
The variability in responses to neoadjuvant treatment with anti-HER2 antibodies prompts to personalized clinical management and the development of innovative treatment strategies. Tumor-infiltrating Natural Killer (TI-NK) cells can predict the efficacy of HER2-targeted antibodies independently from clinicopathological factors in primary HER2-positive breast cancer patients. Understanding the mechanism/s underlying this association would contribute to optimizing patient stratification and provide the rationale for combinatorial approaches with immunotherapy.
We sought to uncover processes enriched in NK cell-infiltrated tumors as compared to NK cell-desert tumors by microarray analysis. Findings were validated in clinical trial-derived transcriptomic data. In vitro and in vivo preclinical models were used for mechanistic studies. Findings were analysed in clinical samples (tumor and serum) from breast cancer patients.
NK cell-infiltrated tumors were enriched in CCL5/IFNG-CXCL9/10 transcripts. In multivariate logistic regression analysis, IFNG levels underlie the association between TI-NK cells and pathological complete response to neoadjuvant treatment with trastuzumab. Mechanistically, the production of IFN- by CD16 + NK cells triggered the secretion of CXCL9/10 from cancer cells. This effect was associated to tumor growth control and the conversion of CD16 into CD16 - CD103 + NK cells in humanized in vivo models. In human breast tumors, the CD16 and CD103 markers identified lineage-related NK cell subpopulations capable of producing CCL5 and IFN- , which correlated with tissue-resident CD8 + T cells. Finally, an early increase in serum CCL5/CXCL9 levels identified patients with NK cell-rich tumors showing good responses to anti-HER2 antibody-based neoadjuvant treatment.
This study identifies specialized NK cell subsets as the source of IFN- influencing the clinical efficacy of anti-HER2 antibodies. It also reveals the potential of serum CCL5/CXCL9 as biomarkers for identifying patients with NK cell-rich tumors and favorable responses to anti-HER2 antibody-based neoadjuvant treatment.
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