Role of polymorphic Fc gamma receptor IIIa and EGFR expression level in cetuximab mediated, NK cell dependent in vitro cytotoxicity of head and neck squamous cell carcinoma cells.
Role of polymorphic Fc gamma receptor IIIa and EGFR expression level in cetuximab mediated, NK cell dependent in vitro cytotoxicity of head and neck squamous cell carcinoma cells.
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DOI：
10.1007/s00262-009-0697-4
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发表时间：
2009-11
期刊：
影响因子：
--
通讯作者：
Ferris RL
中科院分区：
文献类型：
--
作者：
López-Albaitero A;Lee SC;Morgan S;Grandis JR;Gooding WE;Ferrone S;Ferris RL
使用 EGFR 特异性单克隆抗体西妥昔单抗进行免疫治疗对 10-20% 的头颈鳞状细胞癌 (SCCHN) 患者具有临床效果。关于患者对基于西妥昔单抗的免疫疗法的不同临床反应的机制的信息很少，尽管这些信息可能有助于优化基于西妥昔单抗的免疫疗法的设计。我们对这些机制的理解将受益于对影响体外与西妥昔单抗孵育的 SCCHN 细胞的细胞依赖性裂解程度的变量的表征。因此，在本研究中，我们研究了效应NK细胞表达的FcγR IIIa-158基因型、西妥昔单抗浓度和SCCHN细胞的EGFR表达水平在其体外裂解程度和NK细胞活化程度中的作用。在 IIIa 密码子 158 基因分型的 PBMC 或纯化的 CD56+ NK 细胞和表达不同水平 EGFR 的 SCCHN 细胞系已分别用作抗体依赖性细胞毒性 (ADCC) 测定中的效应子和靶标。此外，使用多重 ELISA 分析 ADCC 测定上清液中的细胞因子和趋化因子水平。我们发现SCCHN细胞的裂解程度受到EGFR表达水平、西妥昔单抗浓度和FcγR多态性的影响。表达 FcγR IIIa-158 VV 等位基因的效应细胞在介导 SCCHN 细胞裂解方面比表达 FcγR IIIa VF 和 VV 等位基因的效应细胞显着（P < 0.0001）更有效，表达更高水平的激活标记物 CD69 和 CD107a，并分泌显着（P < 0.05）更大量的炎性细胞因子和趋化因子。 IL-2 或 IL-15 治疗通过不良结合表达 FcγR IIIa 158 FF 的 NK 细胞增加西妥昔单抗介导的 ADCC。 FcγR IIIa-158 多态性在 NK 细胞对 SCCHN 细胞的细胞毒性中的重要性支持了免疫激活的潜在作用，并可以解释西妥昔单抗介导的临床反应的患者变异性。来自患者淋巴细胞的细胞和分泌的免疫谱以及 FcγR 基因型可以为西妥昔单抗治疗的患者提供临床上有用的免疫激活生物标志物。
Immunotherapy with the EGFR-specific mAb cetuximab is clinically effective in 10–20% of patients with squamous cell carcinoma of the head and neck (SCCHN). Little information is available about the mechanism(s) underlying patients’ differential clinical response to cetuximab-based immunotherapy, although this information may contribute to optimizing the design of cetuximab-based immunotherapy. Our understanding of these mechanisms would benefit from the characterization of the variables which influence the extent of cell dependent-lysis of SCCHN cells incubated with cetuximab in vitro. Therefore, in this study we have investigated the role of FcγR IIIa-158 genotype expressed by effector NK cells, cetuximab concentration, and EGFR expression level by SCCHN cells in the extent of their in vitro lysis and in the degree of NK cell activation. PBMC or purified CD56+ NK cells genotyped at IIIa codon 158 and SCCHN cell lines expressing different levels of EGFR have been used as effectors and targets, respectively, in antibody dependent cellular cytotoxicity (ADCC) assays. Furthermore, supernatants from ADCC assays were analyzed for cytokine and chemokine levels using multiplexed ELISA. We found that the extent of lysis of SCCHN cells was influenced by the EGFR expression level, cetuximab concentration, and FcγR polymorphism. Effector cells expressing the FcγR IIIa-158 VV allele were significantly (P < 0.0001) more effective than those expressing FcγR IIIa VF and VV alleles in mediating lysis of SCCHN cells expressed higher levels of the activation markers CD69 and CD107a, and secreted significantly (P < 0.05) larger amounts of inflammatory cytokines and chemokines. IL-2 or IL-15 treatment increased cetuximab-mediated ADCC by poor binding FcγR IIIa 158 FF expressing NK cells. The importance of the FcγR IIIa-158 polymorphism in cytotoxicity of SCCHN cells by NK cells supports a potential role for immune activation and may explain patient variability of cetuximab mediated clinical responses. Cellular and secreted immune profiles and FcγR genotypes from patients’ lymphocytes may provide clinically useful bio-markers of immune activation in cetuximab treated patients.
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影响因子：
3.8
作者：
Linkov, Faina;Lisovich, Alex;Ferris, Robert L.
通讯作者：
Ferris, Robert L.
影响因子：
45.3
作者：
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Levy, R
影响因子：
11.5
作者：
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Whiteside, TL
影响因子：
5.7
作者：
Aerts, Hugo J. W. L.;Dubois, Ludwig;Lambin, Philippe
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影响因子：
5.7
作者：
Wild, R;Fager, K;Rose, WC
通讯作者：
Rose, WC