Augmenting Antitumor Immunity after Allografting

描述（由申请方提供）：本提案的更广泛的长期目标是剖析过继转移供体T细胞在给予已建立的同种异体嵌合体后的同种免疫应答机制，并使用该数据开发临床可转化策略以增强抗肿瘤免疫力。我们的初步研究表明，MHC匹配的同种异体移植后，宿主来源的树突状细胞（DC）坚持在皮肤中，尽管明显的完整的供体DC嵌合体在血液和正在进行的移植物抗白血病（GVL）反应。此外，我们发现供体T细胞过继转移到同种异体MHC匹配的嵌合体中，其中所有血液DC都是供体来源的，可以导致对残留宿主皮肤DC的移植物抗宿主（GVH）反应性。有趣的是，DLI给药的嵌合体，已经局部处理的Toll样受体（TLR）7配体，咪喹莫特，不仅增加了DLI介导的GVH反应性，而且GVL反应。如果与肿瘤疫苗接种结合，这些应答导致治疗动物对肿瘤再攻击表现出回忆应答的能力。因此，该提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全供体嵌合体中诱导同种免疫应答中起主要作用;此外，这些应答的结果可以用定义的分子配体和肿瘤疫苗在体内操纵以产生持久的抗肿瘤免疫。为了研究这一假说，提出了以下具体目标：1）表征MHC匹配的同种异体移植后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对DLI介导的GVH和GVL反应性的作用，并表征TLR介导的信号传导的作用;以及2）确定T细胞/DC相互作用对同种异体移植后疫苗诱导的应答的作用。这些研究将检查残留的宿主皮肤DC和供体血液DC在诱导抗原特异性T细胞和疫苗诱导的免疫中的功能意义。本提案中描述的研究的近期目标是开发可能导致改善抗肿瘤免疫力的新型治疗策略;长期目标是将这些发现转化为临床。 公共卫生相关性：该提议背后的中心假设是供体T细胞和残留的宿主皮肤DC之间的相互作用在移植后完全供体嵌合体中诱导同种免疫应答中起主要作用，并且这些应答的结果可以用限定的分子配体和肿瘤疫苗在体内操纵，从而产生持久的抗肿瘤免疫。因此，所提出的研究的目标是剖析在已建立的MHC匹配的同种异体嵌合体中控制同种免疫应答的机制，并使用该数据来开发临床上可翻译的策略以增强抗肿瘤免疫。

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.