Augmenting Antitumor Immunity after Allografting

描述（由申请人提供）：本提案更广泛、更长期的目标是剖析过继转移供体T细胞在给予已建立的异体嵌合体后的同种免疫反应的控制机制，并利用这些数据开发临床可翻译的策略来增强抗肿瘤免疫。我们的初步研究表明，在mhc匹配的同种异体移植后，宿主来源的树突状细胞（DC）在皮肤中持续存在，尽管血液中存在明显的完全供体DC嵌合和持续的移植物抗白血病（GVL）反应。此外，我们发现供体T细胞过继转移到同种异体mhc匹配嵌合体，其中所有血液dc都来自供体，可导致对残留宿主皮肤dc的移植物抗宿主（GVH）反应。有趣的是，用toll样受体（TLR）7配体咪喹莫特局部处理的嵌合体给予DLI，不仅增强了DLI介导的GVH反应性，而且增强了GVL反应。这些反应，如果与肿瘤疫苗接种相结合，导致治疗动物对肿瘤再攻击表现出记忆反应的能力。因此，该建议的中心假设是供体T细胞/宿主皮肤DC相互作用在移植后完整供体嵌合体诱导同种免疫反应中起主要作用；此外，这些反应的结果可以在体内用确定的分子配体和肿瘤疫苗来操纵，从而产生持久的抗肿瘤免疫。为了研究这一假设，我们提出了以下具体目标：1)表征mhc匹配同种异体移植后T细胞/DC相互作用的细胞和分子机制。这些研究将确定宿主和供体dc在dli介导的GVH和GVL反应中的作用，并表征tlr介导的信号传导的作用；2)确定T细胞/DC相互作用在同种异体移植后疫苗诱导应答中的作用。这些研究将检验宿主皮肤和供体血液中残留的dc在诱导抗原特异性T细胞和疫苗诱导免疫方面的功能意义。本提案中所述研究的直接目标是开发可能导致提高抗肿瘤免疫的新治疗策略；长期目标是将这些发现转化为临床应用。

DESCRIPTION (provided by applicant): The broader, long-term objectives of this proposal are to dissect the mechanisms governing alloimmune responses of adoptively transferred donor T cells after their administration to established allogeneic chimeras and to use this data to develop clinically translatable strategies to augment anti- tumor immunity. Our preliminary studies suggest that after MHC-matched allografting, host-derived dendritic cells (DCs) persist in the skin, despite the apparent full donor DC chimerism in the blood and ongoing graft-versus-leukemia (GVL) responses. Furthermore, we found that adoptive transfer of donor T cells to allogeneic MHC-matched chimeras, in which all blood DCs are of donor origin, can lead to graft-versus-host (GVH) reactivity toward residual host skin DCs. Interestingly, DLI administration to chimeras that have been topically treated with the Toll-like receptor (TLR)7 ligand, imiquimod, not only augmented the DLI-mediated GVH reactivity, but also the GVL response. These responses, if combined with tumor vaccination, resulted in the ability of treated animals to exhibit an anamnestic response to tumor re-challenge. Accordingly, the central hypothesis of this proposal is that donor T cell/host skin DC interactions play a principal role in the induction of an alloimmune response in complete donor chimeras post-transplant; and, moreover, that the outcome of these responses can be manipulated in vivo with defined molecular ligands and tumor vaccines to result in long-lasting anti-tumor immunity. To investigate this hypothesis, the following specific aims are proposed: 1) To characterize the cellular and molecular mechanisms governing T cell/DC interactions post MHC-matched allografting. These studies will determine the roles of host and donor DCs on the DLI-mediated GVH and GVL reactivities and characterize the role of TLR-mediated signaling; and 2) To determine the role of T cell/DC interactions on the vaccine-induced responses after allografting. These studies will examine the functional significance of residual host skin DCs and donor blood DCs on the induction of antigen-specific T cells and vaccine-induced immunity. The immediate goal of the studies described in this proposal is to develop novel therapeutic strategies that may lead to improved anti- tumor immunity; the long-term goal is to translate these findings to the clinic. PUBLIC HEALTH RELEVANCE: The central hypothesis behind this proposal is that interactions between donor T cells and residual host skin DCs play a principal role in the induction of alloimmune responses in complete donor chimeras post-transplant and that outcome of these responses can be manipulated in vivo with defined molecular ligands and tumor vaccine resulting in long-lasting anti-tumor immunity. Thus, the goal of the proposed study is to dissect the mechanisms governing alloimmune responses in established MHC- matched allogeneic chimeras and to use this data to develop clinically translatable strategies to augment anti-tumor immunity.