Immune and Gene Therapy Laboratory, Cancer Centre Karolinska, Department of Oncology-Pathology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Int J Oncol. 2010 Dec;37(6):1599-606. doi: 10.3892/ijo_00000814.
Fcγ receptors (FcγRs) on effector cells are of importance for mediating antibody-dependent cellular cytotoxicity (ADCC). FcγRIIIa158valine (V)/phenylalanine (F) and FcγRIIa131histidine (H)/arginine(R) polymorphisms have been shown to relate to prognosis in antibody-treated patients. The aim of the present study was to analyze the polymorphisms of both FcγRIIIa and FcγRIIa in colorectal carcinoma (CRC) patients receiving either passively administered monoclonal antibodies (MAbs) or antibodies induced by carcinoembryonic antigen (CEA) vaccination. One hundred and thirty CRC patients were included. Thirty-eight patients received adjuvant treatment with an anti-EpCAM monoclonal antibody (edrecolomab) (n=17) or rCEA vaccination therapeutic cancer vaccine (TCV) (n=21) inducing anti-CEA IgG antibodies. Ninety-two patients had metastatic disease and received anti-EpCAM MAb based therapies. FcγR genotypes were analysed using genomic DNA and PCR. ADCC was tested in a standard 18 h Cr51 release assay. In all adjuvant-treated patients, FcγRIIIa158V carriers (V/V and V/F) had a significantly better overall survival compared to F/F homozygous patients (p<0.05), FcγRIIa R carriers vs. H/H (p=0.05) as well as V and R carriers combined compared to the others (p<0.05). Similar findings were obtained when antibody and TCV-treated patients were analysed separately. No impact on the prognosis of FcγR polymorphisms was noted in advanced disease. FcγRIIIa V carriers had a significantly higher ADCC activity compared to F/F patients (p=0.001). Our model study might support the notion that FcγRIIIa V carriers as well as FcγRIIa R carriers receiving adjuvant, passively or actively (TCV)-induced antibody treatment might have a better prognosis than the others. Prospective extended clinical trials are warranted to study the predictive/prognostic impact of FcγR polymorphisms in antibody-treated patients and might be a valuable biomarker to optimize antibody-based treatment strategies.
Fcγ 受体（FcγRs）在效应细胞上对于介导抗体依赖的细胞细胞毒性（ADCC）非常重要。已经表明，FcγRIIIa158 缬氨酸（V）/苯丙氨酸（F）和 FcγRIIa131 组氨酸（H）/精氨酸（R）多态性与抗体治疗患者的预后有关。本研究的目的是分析接受被动给予单克隆抗体（MAbs）或癌胚抗原（CEA）疫苗诱导的抗体治疗的结直肠癌（CRC）患者中 FcγRIIIa 和 FcγRIIa 的多态性。纳入了 130 例 CRC 患者。38 例患者接受抗 EpCAM 单克隆抗体（edrecolomab）（n=17）或 rCEA 疫苗治疗性癌症疫苗（TCV）（n=21）辅助治疗，诱导抗 CEA IgG 抗体。92 例患者患有转移性疾病，并接受了抗 EpCAM MAb 为基础的治疗。使用基因组 DNA 和 PCR 分析 FcγR 基因型。在标准的 18 小时 Cr51 释放测定中测试 ADCC。在所有辅助治疗的患者中，FcγRIIIa158V 携带者（V/V 和 V/F）的总生存明显优于 F/F 纯合子患者（p<0.05），FcγRIIa R 携带者与 H/H 相比（p=0.05）以及 V 和 R 携带者联合与其他相比（p<0.05）。当分别分析抗体和 TCV 治疗的患者时，也得到了类似的发现。在晚期疾病中，FcγR 多态性对预后没有影响。FcγRIIIa V 携带者的 ADCC 活性明显高于 F/F 患者（p=0.001）。我们的模型研究可能支持这样的观点，即接受辅助治疗、被动或主动（TCV）诱导的抗体治疗的 FcγRIIIa V 携带者以及 FcγRIIa R 携带者可能比其他人具有更好的预后。需要进行前瞻性扩展临床试验，以研究 FcγR 多态性在抗体治疗患者中的预测/预后影响，并可能成为优化抗体治疗策略的有价值的生物标志物。
