Anti-Tumor Autoimmunity by lymphopenia T cell Expansion

描述(申请人提供)：由于肿瘤相关抗原主要由正常的未突变基因编码，有效的癌症免疫疗法引发的免疫反应本质上是自身免疫的。然而，打破对自身抗原的耐受性仍然是一个重大挑战。最近的研究表明，在淋巴细胞减少的情况下，外周T细胞增殖以重新建立适当的细胞数量。这种动态平衡的T细胞增殖依赖于自身多肽/MHC配体的识别，并伴随着几个激活标记和效应功能的获得，包括细胞毒性。在此基础上，我们推测，在肿瘤细胞攻击的同时，诱导内稳态T细胞增殖可能是优先扩增和激活原本具有耐受性的淋巴细胞，从而诱导有效的抗肿瘤自身免疫的一种方式。我们对黑色素瘤细胞挑战的淋巴细胞减少症小鼠进行的初步实验表明，确实是这样。在这里，我们希望通过检查临床适用性，特别是这种方法的机制基础来扩展这一新的观察。具体目标包括(A)确定在不同疾病阶段对已建立的肿瘤的稳态T细胞增殖的有效性；(B)探索在T细胞稳态扩增和启动过程中由肿瘤细胞直接提呈与由抗原提呈细胞交叉提呈的作用；(C)评估T细胞选择和打破对肿瘤抗原的耐受性的机制；以及(D)确定是否可以通过补充促进自稳T细胞增殖和存活的营养细胞因子来改善抗肿瘤效果，并增强记忆T细胞的维持。这一结果将明确稳态T细胞增殖在肿瘤自身免疫中的作用，并为癌症的治疗提供新的方法。

DESCRIPTION (provided by applicant): Since tumor-associated antigens are primarily encoded by normal unmutated genes, the immune responses elicited by an effective cancer immunotherapy are essentially autoimmune in nature. However, breaking tolerance for self-antigens remains a major challenge. Recent studies showed that, under lymphopenic conditions, peripheral T cells proliferate to re-establish appropriate cell numbers. Such homeostatic T cell proliferation depends on recognition of self-peptide/MHC ligands and is accompanied by acquisition of several activation markers and effector functions, including cytotoxicity. On this basis, we hypothesized that induction of homeostatic T cell proliferation concurrent with tumor cell challenge may be a way to preferentially expand and activate otherwise tolerant lymphocytes and, hence, elicit effective anti-tumor autoimmunity. Our preliminary experiments with melanoma cell-challenged lymphopenic mice transferred with small numbers of syngeneic T cells indicated that this is indeed the case. Here, we wish to extend this novel observation by examining the clinical applicability, particularly the mechanistic basis of this approach. Specific Aims include (a) defining the efficacy of homeostatic T cell proliferation on established tumors at different disease stages; (b) exploring the role of direct presentation by tumor cells versus cross-presentation by antigen-presenting cells during T cell homeostatic expansion and priming; (c) evaluating mechanisms of T cell selection and break of tolerance for tumor antigens; and (d) determining whether the anti-tumor effect can be improved by supplementing trophic cytokines that promote homeostatic T cell proliferation and survival, and enhance maintenance of memory T cells. The results will define the role of homeostatic T cell proliferation in tumor autoimmunity, and provide new approaches to the treatment of cancer.