Augmenting Antitumor Immunity after Allografting

摘要： 这项建议的更广泛的长期目标是剖析管理 过继转移的供体T细胞在给予建立的免疫系统后的同种免疫应答 同种异体嵌合体，并使用这些数据来开发临床上可翻译的策略，以增加抗- 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， 树突状细胞（DC）持续存在于皮肤中，尽管血液中存在明显的完全供体DC嵌合体， 持续的移植物抗白血病（GVL）反应。此外，我们发现供体的过继转移 T细胞与同种异体MHC匹配的嵌合体，其中所有的血液DC都是供体来源的，可以导致 移植物抗宿主（GVH）反应性对残留的宿主皮肤DC。有趣的是，DLI管理 已经用Toll样受体（TLR）7配体咪喹莫特局部治疗的嵌合体，不仅 增强了DLI介导的GVH反应性，但也增强了GVL反应。这些反应，如果 与肿瘤疫苗接种相结合，导致治疗动物表现出记忆恢复的能力。 对肿瘤再激发的反应。因此，该提议的中心假设是， 手机？宿主皮肤DC相互作用在同种免疫应答的诱导中起主要作用 在移植后的完全供体嵌合体中;而且，这些结果 可以用确定的分子配体和肿瘤疫苗在体内操纵应答， 产生持久的抗肿瘤免疫力。 为了研究这一假设，提出了以下具体目标：1）表征 细胞和分子机制控制T细胞？MHC匹配后的DC相互作用 同种异体移植这些研究将确定宿主和供体DC在DLI介导的GVH中的作用 和GVL反应性并表征TLR介导的信号传导的作用;和2）为了确定TLR介导的信号传导的作用， T细胞的作用？同种异体移植后疫苗诱导反应的DC相互作用。这些 研究将检查残留的宿主皮肤DC和供体血液DC对移植物的功能意义。 抗原特异性T细胞的诱导和疫苗诱导的免疫。研究的直接目标是 在这项建议中描述的是开发新的治疗策略，可能会导致改善抗- 肿瘤免疫;长期目标是将这些发现转化为临床。工作范围： 这一提议背后的核心假设是，供体T细胞和残余T细胞之间的相互作用可能是一种免疫反应。 宿主皮肤DC在诱导完全供体的同种免疫应答中起主要作用 移植后嵌合体，这些反应的结果可以在体内用定义的 分子配体和肿瘤疫苗，产生持久的抗肿瘤免疫。因此， 拟议的研究是剖析在已建立的MHC中控制同种免疫反应的机制， 匹配的同种异体嵌合体，并使用这些数据来开发临床可翻译的策略， 增强抗肿瘤免疫力。

Abstract: 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. Scope of the work: 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.