Tumor rejection antigens induced via epitope spreading

描述（由申请人提供）：人类肿瘤具有免疫原性，许多肿瘤抗原已被确定。肿瘤免疫学家现在面临的一个问题是确定哪些抗原与肿瘤组织的破坏有关，即肿瘤排斥抗原。理想的肿瘤排斥抗原是[1]对肿瘤的潜在生物学至关重要，[2]是由T辅助细胞、细胞溶解T细胞和抗体组成的多方面高强度免疫反应的靶标，[3]是免疫反应赋予治疗益处的靶标。我们实验室之前的研究表明，IV期乳腺癌患者可以成功地接种HER-2/neu （HER2）肽疫苗，从而导致表位扩散并提高生存率。分子内和分子间表位扩散都是免疫的结果。在自身免疫性疾病中，表位扩散与侵袭性组织特异性破坏有关。表位扩散也许可以解释为什么我们的病人存活率提高了。确定在IV期乳腺癌患者群体中发生表位扩散的抗原可能有助于开发靶向和特异性破坏肿瘤组织的癌症疫苗策略。我们的假设是这些抗原可能是肿瘤排斥抗原。本研究的具体目的是：(1)利用经HER2肽疫苗免疫的乳腺癌患者的血清识别潜在的“肿瘤排斥”抗原，这些患者在主动免疫后表现出表位扩散和生存期延长；(2)确定通过血清学筛查确定的抗原是否可以被乳腺癌患者的T细胞识别。

DESCRIPTION (provided by applicant): Human tumors are immunogenic and many tumor antigens have been identified. A problem now facing tumor immunologists is to determine what antigens are relevant to the destruction of tumor tissue, i.e. tumor rejection antigens. Ideal tumor rejection antigens would be ones that [1] are essential to the underlying biology of the tumor, [2] are the targets of a multifaceted immune response of high magnitude consisting of T helper cells, cytolytic T cells, and antibodies, and, [3] those to which an immune response confers therapeutic benefit. Previous studies from our laboratory have shown that stage IV breast cancer patients can be successfully immunized with HER-2/neu (HER2) peptide vaccines resulting in epitope spreading and improved survival. Both intramolecular and intermolecular epitope spreading occurred as a result of immunization. In autoimmune disease, epitope spreading is associated with aggressive tissue specific destruction. Epitope spreading may explain why our patients had improved survival. Identifying those antigens to which epitope spreading occurred in this population of stage IV breast cancer patients may prove useful in developing cancer vaccine strategies to target and specifically destroy tumor tissue. Our hypothesis is that these antigens may be tumor rejection antigens. The specific aims of this proposal are to: (1) identify potential "tumor rejection" antigens using sera derived from breast cancer patients immunized with a HER2 peptide-based vaccine who demonstrated epitope spreading and prolonged survival after active immunization, and, (2) determine whether antigens, identified through serologic screening, can be recognized by T cells derived from breast cancer patients. We will use the technique of serological analysis of recombinant cDNA expression libraries or "SEREX" to screen for tumor-specific antigens that were the result of epitope spreading following immunization. Many of the tumor specific IgG antibody responses identified in this fashion are high titer implying recognition by CD4+ T helper cells. Thus, it is assumed that antigens discovered using antibody immunity as a screening tool can be considered to be recognized by the CD4+ T helper cell repertoire (2) and, potentially, CTL. We will use post-immunization sera derived from Stage IV breast cancer patients that had both improved survival and epitope spreading following immunization with a HER2 peptide vaccine to identify novel immunogenic proteins. New antigens induced by immunization will be identified by "subtraction" of antigens recognized by the pre-vaccine serum. Subsequent studies will determine whether these new antigens, identified via serologic screening, can serve as T cell targets. Our goal is to develop immune-based strategies (e.g. vaccines) that would be associated with tumor destruction and survival benefit.