Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
Oncology Department, Hospital del Mar, Barcelona, Spain.
J Exp Clin Cancer Res. 2024 Jan 3;43(1):10. doi: 10.1186/s13046-023-02918-4.
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-ɣ 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 CD16CD103 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-ɣ, 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-ɣ 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.
曲妥珠单抗等抗 HER2 抗体新辅助治疗的反应存在差异，这促使我们采取个体化的临床管理，并开发新的治疗策略。肿瘤浸润自然杀伤（TI-NK）细胞可预测原发性 HER2 阳性乳腺癌患者接受抗 HER2 抗体治疗的疗效，且独立于临床病理因素。了解这种关联的机制将有助于优化患者分层，并为免疫治疗联合治疗提供依据。
我们通过微阵列分析，试图发现与 NK 细胞荒漠肿瘤相比，NK 细胞浸润肿瘤中富集的过程。在临床试验衍生的转录组数据中验证了这些发现。我们使用体外和体内临床前模型进行了机制研究。对来自乳腺癌患者的临床样本（肿瘤和血清）进行了分析。
NK 细胞浸润肿瘤中 CCL5/IFNG-CXCL9/10 转录本丰富。在多变量逻辑回归分析中，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 细胞产生的 IFN-γ触发癌细胞分泌 CXCL9/10。这种效应与肿瘤生长控制以及在人源化体内模型中 CD16+转化为 CD16+CD103+NK 细胞有关。在人类乳腺癌肿瘤中，CD16 和 CD103 标志物鉴定出具有产生 CCL5 和 IFN-γ能力的谱系相关 NK 细胞亚群，其与组织驻留的 CD8+T 细胞相关。最后，血清 CCL5/CXCL9 水平的早期升高可识别出 NK 细胞丰富的肿瘤患者，对基于抗 HER2 抗体的新辅助治疗反应良好。
本研究鉴定了具有特殊功能的 NK 细胞亚群，作为影响抗 HER2 抗体临床疗效的 IFN-γ来源。它还揭示了血清 CCL5/CXCL9 作为识别 NK 细胞丰富的肿瘤患者和对基于抗 HER2 抗体的新辅助治疗反应良好的生物标志物的潜力。
Zotero 插件
