Cassard Lydie, Cohen-Solal Joël F G, Galinha Annie, Sastre-Garau Xavier, Mathiot Claire, Galon Jérôme, Dorval Thierry, Bernheim Alain, Fridman Wolf H, Sautès-Fridman Catherine
Unité d'Immunologie Cellulaire et Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM) U 255 and Université Pierre et Marie Curie Paris VI, Centre de Recherches Biomédicales des Cordeliers, Paris, France.
J Clin Invest. 2002 Nov;110(10):1549-57. doi: 10.1172/JCI15454.
The efficacy of anti-tumor IgG reflects the balance between opposing signals mediated by activating and inhibitory Fc(gamma) receptors (Fc(gamma)Rs) expressed by effector cells. Here, we show that human malignant melanoma cells express the inhibitory low-affinity Fc(gamma) receptor Fc(gamma)RIIB1 in 40% of tested metastases. When melanoma cells were grafted in nude mice, a profound inhibition of Fc(gamma)RIIB1 tumor growth that required the intracytoplasmic region of the receptor was observed. IgG immune complexes (ICs) may be required for this inhibition, since sera from nude mice bearing tumors contained IgG that decreased the proliferation of Fc(gamma)RIIB1-positive cells in vitro, and tumor development of Fc(gamma)RIIB1-positive melanoma lines was not inhibited in antibody-defective severe combined immunodeficiency (SCID) mice. Passive immunization of SCID mice with anti-ganglioside G(D2) antibody resulted in significant inhibition of growth of Fc(gamma)RIIB1-positive tumors in an intracytoplasmic-dependent manner. Altogether, these data suggest that human melanoma cells express biologically active inhibitory Fc(gamma)RIIB1, which regulates their development upon direct interaction with anti-tumor antibodies. Therefore, Fc(gamma)R expression on human tumors may be one component of the efficacy of antibody-mediated therapies, and Fc(gamma)R-positive tumors could be the most sensitive candidates for such treatments.
抗肿瘤IgG的疗效反映了效应细胞表达的激活型和抑制型Fc（γ）受体（Fc（γ）Rs）介导的相反信号之间的平衡。在此，我们发现人类恶性黑色素瘤细胞在40%的测试转移灶中表达抑制性低亲和力Fc（γ）受体Fc（γ）RIIB1。当将黑色素瘤细胞接种到裸鼠体内时，观察到Fc（γ）RIIB1对肿瘤生长有显著抑制作用，这需要该受体的胞质区域参与。这种抑制作用可能需要IgG免疫复合物（ICs），因为荷瘤裸鼠的血清中含有IgG，其在体外可降低Fc（γ）RIIB1阳性细胞的增殖，并且在抗体缺陷的严重联合免疫缺陷（SCID）小鼠中，Fc（γ）RIIB1阳性黑色素瘤细胞系的肿瘤发展未受到抑制。用抗神经节苷脂G（D2）抗体对SCID小鼠进行被动免疫，以胞质依赖的方式显著抑制了Fc（γ）RIIB1阳性肿瘤的生长。总之，这些数据表明人类黑色素瘤细胞表达具有生物活性的抑制性Fc（γ）RIIB1，其通过与抗肿瘤抗体直接相互作用来调节肿瘤的发展。因此，人类肿瘤上Fc（γ）R的表达可能是抗体介导治疗疗效的一个组成部分，而Fc（γ）R阳性肿瘤可能是此类治疗最敏感的候选对象。
