Immunization Against Melanoma Differentiation Antigens

描述（由申请人提供）：免疫系统在黑色素瘤和其他癌症上识别分化抗原形式的自身抗原和突变形式的改变的自身抗原。虽然突变是肿瘤特异性抗原的公认基础，但我们和其他人已经表明，对分化抗原的识别也与对癌症的免疫有关。识别这些抗原存在问题，特别是如何克服免疫耐受。我们已经使用小鼠黑色素瘤模型来显示小鼠可以耐受分化抗原的酪氨酸酶家族。用抗原的异种直向同源物免疫可以暂时打破耐受性。然而，我们的初步结果表明，CD4+细胞群和B细胞抑制免疫反应黑色素瘤。我们的第一个目标是解决的作用，CD4+和B细胞抑制肿瘤免疫和记忆反应，特别是不同的行动：抗原。我们接下来的两个目标转向突变的免疫识别的后果。我们已经开发了创建突变分化抗原的组合文库的方法，以解决什么类型的突变可以导致针对非突变亲本抗原的自身免疫（目的2）以及什么类型的突变可以直接导致肿瘤免疫（目的3）。在目标4中，我们将继续建立更多相关的黑色素瘤小鼠模型，这些模型发展为内源性侵袭性黑色素瘤，以研究针对分化和突变抗原的肿瘤免疫。

DESCRIPTION (provided by applicant): Self antigens, in the form of differentiation antigens, and altered self antigens, in the form of mutations, are recognized on melanoma and other cancers by the immune system. Although mutations are an accepted basis for tumor-specific antigens, we and others have shown that recognition of differentiation antigens is also relevant to immunity to cancer. Recognition of these antigens presents problems, especially how one can overcome immune tolerance. We have used a mouse melanoma model to show that mice can be tolerant to the tyrosinase family of differentiation antigens. Tolerance can temporarily be broken by immunization with xenogeneic orthologues of antigen. However, our preliminary results suggest that a CD4+ cell population and B cells suppress immune responses to melanoma. Our first aim addresses the role of CD4+ and B cells n suppressing tumor immunity and memory responses, particularly to different action: antigens. Our next two aims turn to the consequences of immune recognition of mutations. We have developed methods to create combinatorial libraries of mutated differentiation antigens to address what types of mutations can lead to autoimmunity against the non-mutated parental antigen (aim 2) and what type of mutations can lead directly to tumor immunity (aim 3). In aim 4, we will continue to create more relevant mouse models of melanoma that develop endogenous invasive melanomas to study tumor immunity against differentiation and mutant antigens.