Takechi Y, Hara I, Naftzger C, Xu Y, Houghton A N
The Swim Across America Laboratory, Memorial Sloan-Kettering Cancer Center, and Cornell University Medical College, New York, NY 10021, USA.
Clin Cancer Res. 1996 Nov;2(11):1837-42.
Differentiation antigens on cancer cells are recognized by the immune system. A prototype set of these autoantigens in melanoma cells are the melanosomal glycoproteins, expressed in both melanomas and normal melanocytes. These are intracellular proteins that can be recognized by both antibodies and T lymphocytes. While one can understand how T cells can respond to intracellular proteins, based on cellular requirements for antigen processing and presentation, it is more difficult to understand how antibody responses to melanosomal proteins could lead to tumor rejection. We demonstrate that gp75 is expressed on the cell surface as well as intracellularly in human and mouse melanomas. The surface expression of gp75 can be augmented by IFN-gamma and during tumor growth in vivo. Surface expression of gp75 on mouse melanoma cells correlates with the ability of a monoclonal antibody (mAb) against gp75 to reject melanomas in syngeneic mice. Antibody-mediated rejection seems to require the Fc portion of the antibody, suggesting a role for Fc receptor-positive effector cells such as natural killer cells. However, although NK1.1(+) cells have been implicated in antibody-induced rejection in vivo, cell surface expression of gp75(+) on melanoma does not lead to susceptibility to antibody-dependent cellular cytotoxicity in vitro. The mAb to gp75 induced tumor rejection in mice carrying both scid and bg/bg traits, showing that neither thymus-dependent T cells nor natural killer cytotoxic activity was required in vivo. Long-term treatment of mice with mAb led to patchy depigmentation in the coat. In summary, an intracellular organellar protein can be expressed at the cell surface and provide an antigenic target for antibody therapy and autoimmunity.
癌细胞上的分化抗原可被免疫系统识别。黑色素瘤细胞中这类自身抗原的一个典型集合是黑素体糖蛋白，在黑色素瘤和正常黑素细胞中均有表达。这些是细胞内蛋白，可被抗体和T淋巴细胞识别。虽然基于抗原加工和呈递的细胞需求，人们可以理解T细胞如何对细胞内蛋白作出反应，但更难理解的是针对黑素体蛋白的抗体反应如何导致肿瘤排斥。我们证明，gp75在人和小鼠黑色素瘤的细胞表面以及细胞内均有表达。gp75的表面表达可被γ干扰素增强，且在体内肿瘤生长过程中也会增强。小鼠黑色素瘤细胞上gp75的表面表达与抗gp75单克隆抗体（mAb）在同基因小鼠中排斥黑色素瘤的能力相关。抗体介导的排斥似乎需要抗体的Fc部分，这表明Fc受体阳性效应细胞如自然杀伤细胞发挥了作用。然而，尽管NK1.1(+)细胞在体内抗体诱导的排斥中起作用，但黑色素瘤上gp75(+)的细胞表面表达在体外并不会导致对抗体依赖性细胞毒性的易感性。针对gp75的mAb在同时具有scid和bg/bg特征的小鼠中诱导肿瘤排斥，表明体内既不需要胸腺依赖性T细胞，也不需要自然杀伤细胞的细胞毒性活性。用mAb长期治疗小鼠会导致其皮毛出现斑驳的色素脱失。总之，一种细胞内细胞器蛋白可以在细胞表面表达，并为抗体治疗和自身免疫提供抗原靶点。
