Translational Tumor Immunology Program, National Institutes on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, United States.
Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
Oral Oncol. 2019 Mar;90:38-44. doi: 10.1016/j.oraloncology.2019.01.017. Epub 2019 Feb 1.
High affinity natural killer cells (haNKs) are a cell therapy product capable of mediating both direct and antibody-dependent cell-mediated cytotoxicity (ADCC). These cells may be particularly useful in tumors that escape T-cell anti-tumor immunity by harboring antigen processing and presentation defects. Here, we demonstrated that haNKs directly kill both HPV-positive and negative head and neck squamous cell carcinoma cells. Variable tumor cell sensitivity to haNK direct cytotoxicity did not correlated with MHC class I chain-related protein A or B (MICA or MICB) expression. Importantly, haNK killing was significantly enhanced via ADCC mediated by cetuximab or avelumab in cells with higher baseline EGFR or PD-L1 expression, respectively. The ability of IFNγ to induce tumor cell PD-L1 expression correlated with enhanced PD-L1-specific ADCC. IFNγ induced neither tumor cell EGFR expression nor EGFR-specific ADCC. Although a single dose of 8 Gy IR did not appear to directly enhance susceptibility to haNK killing alone, enhanced PD-L1- and EGFR-mediated ADCC after IR correlated with increased PD-L1 and EGFR expression in one of four models. This pre-clinical evidence supports the investigation of haNK cellular therapy in combination with ADCC-mediating mAbs, with or without IR, in the clinical trial setting for patients with advanced HNSCCs. Given the MHC-unrestricted nature of this treatment, it may represent an opportunity to treat patients with non-T-cell inflamed tumors.
高亲和力自然杀伤细胞（haNK 细胞）是一种细胞治疗产品，能够介导直接杀伤和抗体依赖性细胞介导的细胞毒性（ADCC）。这些细胞在那些存在抗原加工和呈递缺陷从而逃避 T 细胞抗肿瘤免疫的肿瘤中可能特别有用。在这里，我们证明 haNK 细胞可以直接杀伤 HPV 阳性和阴性的头颈部鳞状细胞癌（HNSCC）细胞。haNK 直接细胞毒性对肿瘤细胞的敏感性变化与 MHC Ⅰ类链相关蛋白 A 或 B（MICA 或 MICB）的表达无关。重要的是，通过与西妥昔单抗或avelumab 介导的 ADCC，haNK 杀伤在基线 EGFR 或 PD-L1 表达较高的细胞中显著增强，分别。IFNγ 诱导肿瘤细胞 PD-L1 表达的能力与增强的 PD-L1 特异性 ADCC 相关。IFNγ 既不诱导肿瘤细胞 EGFR 表达，也不诱导 EGFR 特异性 ADCC。虽然单次 8GyIR 照射似乎并没有直接增强 haNK 杀伤的敏感性，但在四种模型中的一种中，IR 后增强的 PD-L1 和 EGFR 介导的 ADCC 与 PD-L1 和 EGFR 表达增加相关。这一临床前证据支持在临床试验中研究 haNK 细胞治疗与 ADCC 介导的单克隆抗体联合应用，无论是否联合 IR，用于治疗晚期 HNSCC 患者。鉴于这种治疗的 MHC 非限制性性质，它可能为治疗非 T 细胞浸润性肿瘤的患者提供了机会。
