Immunity and Infection, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain.
Cancer Research Program, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain.
Cancer Immunol Res. 2019 Aug;7(8):1280-1292. doi: 10.1158/2326-6066.CIR-18-0896. Epub 2019 Jun 12.
Natural killer (NK) cells can orchestrate effective antitumor immunity. The presence of tumor-infiltrating NK cells in diagnostic biopsies predicts pathologic complete response (pCR) to HER2-specific therapeutic antibodies in patients with primary breast cancer. Here, we analyzed whether diversity in circulating NK cells might influence tumor infiltration and HER2-specific therapeutic antibody efficacy. We found that numbers of circulating CD57 NK cells inversely correlated with pCR to HER2-specific antibody treatment in patients with primary breast cancer independently of age, traditional clinicopathologic factors, and CD16A 158F/V genotype. This association was uncoupled from the expression of other NK-cell receptors, the presence of adaptive NK cells, or changes in major T-cell subsets, reminiscent of cytomegalovirus-induced immunomodulation. NK-cell activation against trastuzumab-coated HER2 breast cancer cells was comparable in patients with high and low proportions of CD57 NK cells. However, circulating CD57 NK cells displayed decreased CXCR3 expression and CD16A-induced IL2-dependent proliferation Presence of CD57 NK cells was reduced in breast tumor-associated infiltrates as compared with paired peripheral blood samples, suggesting deficient homing, proliferation, and/or survival of NK cells in the tumor niche. Indeed, numbers of circulating CD57 were inversely related to tumor-infiltrating NK-cell numbers. Our data reveal that NK-cell differentiation influences their antitumor potential and that CD57 NK cells may be a biomarker useful for tailoring HER2 antibody-based therapeutic strategies in breast cancer.
自然杀伤 (NK) 细胞可以协调有效的抗肿瘤免疫。在原发性乳腺癌患者的诊断性活检中存在肿瘤浸润 NK 细胞，可预测对 HER2 特异性治疗性抗体的病理完全缓解 (pCR)。在这里，我们分析了循环 NK 细胞的多样性是否可能影响肿瘤浸润和 HER2 特异性治疗性抗体的疗效。我们发现，循环 CD57 NK 细胞的数量与原发性乳腺癌患者对 HER2 特异性抗体治疗的 pCR 呈负相关，与年龄、传统临床病理因素和 CD16A 158F/V 基因型无关。这种关联与其他 NK 细胞受体的表达、适应性 NK 细胞的存在或主要 T 细胞亚群的变化无关，使人联想到巨细胞病毒诱导的免疫调节。对曲妥珠单抗包被的 HER2 乳腺癌细胞的 NK 细胞激活在 CD57 NK 细胞比例高和低的患者中相似。然而，循环 CD57 NK 细胞表现出降低的 CXCR3 表达和 CD16A 诱导的 IL2 依赖性增殖。与配对的外周血样本相比，CD57 NK 细胞在乳腺肿瘤相关浸润物中的存在减少，表明 NK 细胞在肿瘤微环境中的归巢、增殖和/或存活不足。事实上，循环 CD57 的数量与肿瘤浸润 NK 细胞的数量呈负相关。我们的数据揭示了 NK 细胞分化会影响其抗肿瘤潜能，并且 CD57 NK 细胞可能是一种有用的生物标志物，可用于调整乳腺癌中基于 HER2 抗体的治疗策略。
