Cassard Lydie, Cohen-Solal Joel F G, Fournier Emilie M, Camilleri-Broët Sophie, Spatz Alain, Chouaïb Salem, Badoual Cécile, Varin Audrey, Fisson Sylvain, Duvillard Pierre, Boix Charlotte, Loncar Shannon M, Sastre-Garau Xavier, Houghton Alan N, Avril Marie-Françoise, Gresser Ion, Fridman Wolf H, Sautès-Fridman Catherine
INSERM, U872, Microenvironnement immunitaire et tumeurs, Equipe 13, Centre de Recherche des Cordeliers, Paris, France.
Int J Cancer. 2008 Dec 15;123(12):2832-9. doi: 10.1002/ijc.23870.
During melanoma progression, patients develop anti-tumor immunity including the production of anti-tumor antibodies. Although the strategies developed by malignant cells to escape anti-tumor cellular immunity have been extensively investigated, little is known about tumor resistance to humoral immunity. The main effect of IgG antibodies is to activate the immune response by binding to host Fc gamma receptors (FcgammaR) expressed by immune cells. We previously reported in a limited study that some human metastatic melanoma cells ectopically express the FcgammaRIIB1, an inhibitory isoform of FcgammaR. By analyzing a large panel of different types of human primary and metastatic solid tumors, we report herein that expression of FcgammaRIIB is restricted to melanoma and is acquired during tumor progression. We show that FcgammaRIIB expression prevents the lysis of human metastatic melanoma cells by NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) in vitro, independently of the intracytoplasmic region of FcgammaRIIB. Using experimental mouse models, we demonstrate that expression of FcgammaRIIB protects B16F0 melanoma tumors from the ADCC induced by monoclonal and polyclonal anti-tumor IgG in vivo. Thus, our results identify FcgammaRIIB as a marker of human metastatic melanoma that impairs the tumor susceptibility to FcgammaR-dependent innate effector responses.
在黑色素瘤进展过程中，患者会产生抗肿瘤免疫，包括产生抗肿瘤抗体。尽管恶性细胞逃避抗肿瘤细胞免疫所采用的策略已得到广泛研究，但对于肿瘤对体液免疫的抗性却知之甚少。IgG抗体的主要作用是通过与免疫细胞表达的宿主Fcγ受体（FcgammaR）结合来激活免疫反应。我们先前在一项有限的研究中报告称，一些人类转移性黑色素瘤细胞异位表达FcγRIIB1，这是FcγR的一种抑制性亚型。通过分析大量不同类型的人类原发性和转移性实体瘤，我们在此报告FcγRIIB的表达仅限于黑色素瘤，且在肿瘤进展过程中获得。我们表明，FcγRIIB的表达可在体外阻止自然杀伤细胞介导的抗体依赖性细胞毒性（ADCC）对人类转移性黑色素瘤细胞的裂解，且与FcγRIIB的胞质区域无关。使用实验性小鼠模型，我们证明FcγRIIB的表达可在体内保护B16F0黑色素瘤肿瘤免受单克隆和多克隆抗肿瘤IgG诱导的ADCC作用。因此，我们的结果确定FcγRIIB是人类转移性黑色素瘤的一个标志物，它会损害肿瘤对FcγR依赖性先天性效应反应的敏感性。
