CD70 Mediated Costimulation of T Cell Responses

具体目标： 基于免疫的疗法为放疗或化疗耐药提供了一种有前景的替代治疗方法 肿瘤，但热情是缓和的事实，一贯成功的治疗病人， 仍然难以捉摸失败的原因可能是多方面的，从免疫战略 产生相对较弱的T细胞反应，对抗炎环境和相关的 免疫抑制机制往往在肿瘤内演变。我们的长远目标 研究的目的是研究免疫调节剂，可用于增强免疫调节剂的强度和功能。 T细胞靶向肿瘤的能力。一种这样的调节剂是CD 70，其是TNF超家族的成员 共刺激分子的TNFSF，其受体是CD 27。我们和其他人最近 证明了CD 70是树突状细胞（DC）的重要组成部分，DC已被授权 活化的CD 4 + T细胞（TCD 4）。作为检查CD 70用于肿瘤免疫治疗的功效的前奏，在 在上一个资助期，我们研究了DC诱导CD 70表达的机制， 以及随后CD 70介导的共刺激对TCD 4和CD 8 + T细胞（TCD 8）的影响。基于 我们观察到1）通过结合CD 40和TLR在体内DC上有效诱导CD 70，2） 阻断CD 70介导的共刺激降低效应TCD 8的存活和分化，以及3）阻断 CD 70介导的共刺激降低了IFN？产生效应TCD 4，我们现在 假设导致诱导CD 70表达或引入CD 27- 激动剂（以可溶性CD 70或激动性抗CD 27抗体的形式）将导致增强的对 通过支持肿瘤特异性T细胞的存活和功能活性来抑制肿瘤生长。为了验证这一 根据这一假设，我们提出以下具体目标： 具体目的1：确定CD 70是否是DC表达的关键免疫原性分子 通过CD 40依赖性和非依赖性途径激活。 我们将确定TLR配体与CD 40激动剂和/或TCD 4协同诱导表达的能力， CD70我们将确定其他免疫刺激分子单方面诱导CD 70的能力。 表达，或与CD 40介导的刺激合作。我们将确定相对免疫原性 以这些方式刺激的DC，并定义免疫原性的任何增强的程度。 依赖于CD 70表达。 具体目的2：确定CD 27激动剂是否增强TH 1分化的TCD 4 我们将分析CD 70介导的共刺激对肿瘤大小和分化状态的影响。 原发性和继发性TCD 4应答。我们将确定CD 70介导的共刺激在多大程度上 可用于增强TCD 4分化为IFN？分泌效应细胞。 具体目标3：确定CD 27激动剂是否增强效应子TCD 8应答。我们将测试 假设CD 27激动剂可以增强原发性TCD 8应答并导致完全TCD 8应答的产生， 功能性记忆TCD 8在存在或不存在TCD 4的情况下。我们将扩大这些研究， CD 27-激动剂支持回忆TCD 8应答。我们将确定CD 70介导的 共刺激有助于效应或记忆前体TCD 8的分化。 具体目的4：确定诱导CD 70或CD 27激动剂是否可以增强 黑色素瘤的免疫控制。我们将评估CD 27激动剂支持治疗的能力。 肿瘤控制在两个不同的方式。首先，我们将通过刺激内源性DC诱导CD 70表达， 通过CD 40和TLR。其次，我们将利用可溶性CD 70或抗CD 27来支持疫苗诱导的TCD 4 和TCD 8或过继转移的T细胞群。 从这些研究中，我们预期将对CD 27激动剂用于以下目的的潜力进行全面评估： 癌症治疗以及对CD 70表达和共刺激的生物学的更好理解。

Specific Aims: Immune-based therapies offer a promising alternative treatment to radiotherapy- or chemotherapyresistant tumors, but enthusiasm is tempered by the fact that consistently successful treatment of patients has remained elusive. The reasons for this failure are likely multifaceted, and range from immunization strategies that generate relatively weak T cell responses, to the anti-inflammatory environment and associated mechanisms of immune suppression that tend to evolve within tumors. The broad, long-term objective of our research is to investigate immune modulators that can be used to enhance the magnitude and functional capacity of T cells that are targeted to tumors. One such modulator is CD70, a member of the TNFsuperfamily (TNFSF) of costimulatory molecules, whose receptor is CD27. We and others have recently demonstrated CD70 as being an important component of a dendritic cell (DC) that has been ¿licensed¿ by activated CD4+ T cell (TCD4). As a prelude to examining the efficacy of CD70 for tumor immunotherapy, during the last funding period we have studied the mechanisms by which the expression of CD70 is induced upon DC, and the subsequent influence of CD70-mediated costimulation on TCD4 and CD8+ T cells (TCD8). Based on our observations that 1) CD70 is potently induced on DC in vivo by engaging both CD40 and TLR, 2) that blocking CD70-mediated costimulation reduces the survival and differentiation of effector TCD8 and 3) blocking CD70-mediated costimulation reduces the magnitude and IFN?-production of effector TCD4, we now hypothesize that interventions that cause the induction of CD70 expression, or the introduction of CD27- agonists (in the form of soluble CD70 or agonistic anti-CD27 antibodies) will result in enhanced control of tumor outgrowth by supporting the survival and functional activity of tumor-specific T cells. To test this hypothesis, we propose the following specific aims: Specific Aim 1: To determine whether CD70 is the critical immunogenic molecule expressed by DC activated by CD40-dependent and independent pathways. We will define the ability of TLR-ligands to synergize with CD40 agonists and/or TCD4 to induce the expression of CD70. We will determine the capacity of other immunostimulatory molecules to unilaterally induce CD70 expression, or cooperate with CD40-mediated stimulation. We will determine the relative immunogenicity of DC stimulated in these manners, and define the extent to which any enhancements to immunogenicity are dependent upon CD70 expression. Specific Aim 2: To determine whether CD27 agonists enhance TH1-differentiated TCD4 We will dissect the impact of CD70-mediated costimulation on the magnitude and differentiation status of primary and secondary TCD4 responses. We will determine the extent to which CD70-mediated costimulation can be utilized to enhance differentiation of TCD4 into IFN?-secreting effector cells. Specific Aim 3: To determine whether CD27 agonists enhance effector TCD8 responses. We will test the hypothesis that CD27 agonists can enhance primary TCD8 responses and lead to the generation of fully functional memory TCD8 in the presence or absence of TCD4. We will extend these studies to address whether CD27-agonists support recall TCD8 responses. We will determine the extent to which CD70-mediated costimulation contributes to the differentiation of effector or memory precursor TCD8. Specific Aim 4: To determine whether induction of CD70 or CD27-agonists can enhance immunological control of melanoma. We will assess the capacity of CD27 agonists to support therapeutic tumor control in two distinct manners. First, we will induce CD70 expression on endogenous DC by stimulation via CD40 and TLR. Second, we will utilize soluble CD70 or anti-CD27 to support either vaccine induced TCD4 and TCD8 or adoptively transferred T cell populations. From these studies we anticipate a thorough evaluation of the potential for CD27-agonists to be used for cancer therapy and also a greater understanding of the biology of CD70 expression and costimulation.