Dynamics of tolerance induction to tumor associated antigens

描述（由申请人提供）：对自身抗原的免疫耐受是许多重要临床情况（如癌症）的关键问题。大多数肿瘤抗原是在肿瘤细胞中重新表达的自体抗原，对这种“新自体抗原”产生的耐受性允许肿瘤生长。几乎可以肯定，对耐受性诱导的微妙之处认识不足是癌症免疫疗法收效甚微的主要原因。虽然第一次抗原接触的时间是产生移植物耐受性或口服耐受性的关键决定因素，但在生命的不同阶段对自身抗原表达的耐受性仍有待了解。我们已经开发了一种转基因模型，其中单拷贝替代自身抗原（Tac）在甲状腺中有条件地表达。将定义明确的CD8 T细胞、CD4 T细胞和B细胞表位置于替代自身抗原中，以评估特异性免疫反应。我们的初步研究表明，胚胎抗原表达导致CD8 T细胞的强耐受性，而成人抗原延迟CD8 T细胞的耐受性。在这个应用中，我们将通过评估CD4 T细胞和B细胞对条件表达Tac转基因的耐受性来继续探索这个模型。基于初步数据，我们推测在不同发育阶段诱导T细胞耐受可能涉及不同的机制，如胚胎抗原的中枢机制和成年抗原的外周机制。使用多种技术，我们将研究在各种条件下发挥作用的容忍机制。可诱导的转基因模型也可用于表示肿瘤相关抗原（TAA）或肿瘤特异性抗原（TSA）在肿瘤转化前或肿瘤转化时的出现。在具有Tac+肿瘤细胞的肿瘤攻击模型中，Tac抗原在先前Tac表达的小鼠中作为TAA，而在先前Tac未表达的小鼠中作为TSA。将通过肿瘤生长来评估抗肿瘤活性，并评估每组小鼠的特异性免疫反应。我们预测先前的抗原表达在不同程度上损害抗肿瘤活性，这取决于初始抗原表达的时间。TSA被认为是癌症免疫治疗的更好靶点，但我们假设长期表达TSA可能导致对TSA的耐受。更好地理解对正常和肿瘤细胞中表达的自身抗原的耐受性诱导可能会导致癌症免疫治疗的关键创新。公共卫生相关性：一个多世纪以来，研究人员和临床医生一直试图利用免疫系统来攻击癌症。在极少数情况下，结果是惊人的成功，但大多数情况下，结果是令人失望的。问题的很大一部分是肿瘤是“自我”的一部分，因此受制于诱导对肿瘤细胞耐受的机制。对耐受性的更好理解将指向打破对肿瘤细胞耐受性的创新方法，从而导致癌细胞的攻击。本应用着重于诱导耐受性，因为它直接关系到对癌症的免疫反应。

DESCRIPTION (provided by applicant): Immune tolerance to self-antigens is the key issue in many important clinical situations, such as cancers. Most tumor antigens are self-antigens de novo expressed in tumor cells, the tolerance that develops to such "neo self-antigens" permit tumor growth. Poor appreciation for the subtleties of tolerance induction is almost certainly a major reason why cancer immunotherapy has met with limited success. Although the timing of first antigen contact is a critical determinant for generating graft tolerance or oral tolerance, much remains to be understood regarding tolerance to self-antigens expressed during different phases of life. We have developed a transgenic model in which a single-copy surrogate autoantigen (Tac) is conditionally expressed in the thyroid. The well defined CD8 T cell, CD4 T cell and B cell epitopes are placed into the surrogate autoantigen for assessing specific immune responses. Our preliminary studies suggest that embryonic antigen expression results in strong CD8 T cell tolerance while adult antigen delays the CD8 T cell tolerance. In this application, we will continue to explore this model by assessing CD4 T cell and B cell tolerance to conditionally expressed Tac transgene. Based on the preliminary data, we hypothesize that different mechanisms may be involved in the induction of T cell tolerance at different developmental stages, e.g. central mechanisms for embryonic antigen and peripheral mechanisms for adult antigen. Using a variety of techniques, we will investigate the tolerance mechanisms that play a role under various conditions. The inducible transgenic model can also be used to represent the appearance of a tumor-associated antigen (TAA) or tumor specific antigen (TSA) before or at the time of neoplastic transformation. In tumor challenge models with Tac+ tumor cells, the Tac antigen will serve as a TAA in mice with previous Tac expression but as a TSA in mice without previous Tac expression. The anti-tumor activity will be assessed by tumor growth and specific immune responses will be evaluated in each group of mice. We predict that previous antigen expression impairs anti-tumor activity to different extents, depending upon the timing of initial antigen expression. TSA has been considered as a better target for cancer immunotherapy, but we hypothesize that long-term TSA expression may result in tolerance to TSA. A better understanding of tolerance induction to self-antigens expressed in normal and tumor cells may lead to key innovations in cancer immunotherapy. PUBLIC HEALTH RELEVANCE: For over a century researchers and clinicians have attempted to use the immune system to attack cancers. On rare occasions results have been stunningly successful but most of the time they have been disappointing. A large part of the problem is that tumors are part of "self" and are therefore subject to mechanisms that induce tolerance to the tumor cells. A better understanding of tolerance would point to innovative ways of breaking tolerance to tumor cells, leading of attack of cancer cells. This application focuses upon the induction of tolerance as it directly relates to immune responses to cancer.