Taylor Rodney J, Chan Siaw-Lin, Wood Aaron, Voskens Caroline J, Wolf Jeffrey S, Lin Wei, Chapoval Andrei, Schulze Dan H, Tian Guoliang, Strome Scott E
Department of Otorhinolaryngology/Head and Neck Surgery, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
Cancer Immunol Immunother. 2009 Jul;58(7):997-1006. doi: 10.1007/s00262-008-0613-3. Epub 2008 Nov 1.
The interaction of Fc fragments of antibodies with the Fcgamma receptors is an essential checkpoint in antibody-dependent cellular cytotoxicity (ADCC). Specific polymorphisms at position 158 enhance FcgammaRIIIa affinity for IgG1 and are associated with improved clinical outcome in lymphoma patients treated with IgG1 anti-CD20 antibody. The role of ADCC in the therapeutic effects of the alpha-epidermal growth factor receptor (EGFR) mAb, cetuximab, in patients with squamous cell carcinoma of the head and neck (SCCHN) is poorly defined. We employed three SCCHN cell lines to test two hypotheses: (1) SCCHN is susceptible to cetuximab-mediated ADCC, (2) efficacy of ADCC is associated with polymorphisms at position 158 of FcgammaRIIIa.
FcgammaRIIIa-158 polymorphisms were determined for healthy donors, and their purified NK cells were used as effector cells against three SCCHN cell lines in ADCC assays. Cytotoxicity levels were compared for each polymorphism class. Proliferation and cell cycle assays were done to examine the direct effects of cetuximab.
Our results indicate that SCCHN is susceptible to cetuximab-mediated ADCC in vitro. NK cytotoxic efficiency correlates with donor 158-polymorphisms in FcgammaRIIIa. Overall cytotoxicity was greatest for individuals having a single V allele when compared to homozygous F/F individuals; the cumulative percent cytotoxicity for each polymorphism among the cell lines was 58.2% V/V, 50.6% V/F, and 26.1% F/F (P < 0.001). Additionally, the presence of a V allele correlated with superior natural cytotoxicity against NK sensitive targets.
These data have both prognostic and therapeutic relevance and support the design of a prospective trial to determine the influence of FcgammaRIIIa polymorphisms on the clinical outcome of patients with SCCHN treated with alpha-EGFR mAbs.
抗体的Fc片段与Fcγ受体的相互作用是抗体依赖的细胞毒性作用（ADCC）中的一个关键检查点。158位的特定多态性增强了FcγRIIIa对IgG1的亲和力，并与接受IgG1抗CD20抗体治疗的淋巴瘤患者的临床预后改善相关。ADCC在α-表皮生长因子受体（EGFR）单克隆抗体西妥昔单抗对头颈部鳞状细胞癌（SCCHN）患者的治疗效果中的作用尚不明确。我们采用三种SCCHN细胞系来检验两个假设：（1）SCCHN对西妥昔单抗介导的ADCC敏感；（2）ADCC的疗效与FcγRIIIa 158位的多态性相关。
测定健康供体的FcγRIIIa-158多态性，并将其纯化的自然杀伤（NK）细胞用作ADCC试验中针对三种SCCHN细胞系的效应细胞。比较每种多态性类别的细胞毒性水平。进行增殖和细胞周期试验以检测西妥昔单抗的直接作用。
我们的结果表明SCCHN在体外对西妥昔单抗介导的ADCC敏感。NK细胞毒性效率与供体FcγRIIIa中的158-多态性相关。与纯合F/F个体相比，具有单个V等位基因的个体的总体细胞毒性最大；各细胞系中每种多态性的累积细胞毒性百分比分别为58.2% V/V、50.6% V/F和26.1% F/F（P < 0.001）。此外，V等位基因的存在与对NK敏感靶标的更高自然细胞毒性相关。
这些数据具有预后和治疗相关性，并支持设计一项前瞻性试验以确定FcγRIIIa多态性对接受α-EGFR单克隆抗体治疗的SCCHN患者临床预后的影响。
