Integrating Innate & Adaptive Immunity in Cancer Therapy

描述(由申请人提供)：IL-12和GM-CSF从可生物降解的微球缓慢释放到单个原发肿瘤结节中，促进了强大的全身抗肿瘤免疫的发展，并在转移的小鼠肿瘤模型中完全根除了播散性肿瘤结节。在这个模型中，调节系统性疾病根除的免疫机制还没有被定义。我们的假设是，局部和持续的IL-12和GM-CSF释放到肿瘤微环境中，促进了肿瘤相关效应记忆T细胞的激活，然后启动了一系列局部炎症事件，导致全身抗肿瘤免疫的发展。为此，在目标1中，我们将从表型和功能上定义存在于原发肿瘤微环境中的T细胞，并描述其激活后的下游事件。在Aim 2中提出的研究将解决持续的假设，即原发肿瘤内炎症活动的诱导将启动长期系统性抗肿瘤T细胞反应的发展，从而有效地渗透和抑制转移肿瘤。 初步观察表明，全身NKT/NK细胞反应也参与了转移肿瘤的抑制。在目标3中，我们将测试这样一个概念，即系统性但短暂的NKT/NK反应的激活伴随着早期的局部免疫事件，以及共同诱导先天免疫和获得性免疫对于有效根除系统性疾病至关重要。最后，在目标4中，我们将测试这样一个假设，即在原发肿瘤微环境中诱导的即刻效应记忆T细胞反应的强度决定了个体小鼠的长期治愈效果。来自这些研究的信息有望为设计一种有效的、基于细胞因子的免疫治疗策略来治疗癌症患者提供有价值的见解。

DESCRIPTION (provided by applicant): The slow release of IL-12 and GM-CSF from biodegradable microspheres into a single primary tumor nodule promotes the development of potent systemic anti-tumor immunity and the complete eradication of disseminated tumor nodules in a metastatic murine tumor model. The immune mechanisms that mediate the eradication of systemic disease have not yet been defined in this model. Our hypothesis is that the local and sustained release of IL-12 and GM-CSF into the tumor microenvironment promotes the activation of the tumor-associated effector memory T-cells, which then initiate a cascade of local inflammatory events that result in the development of a systemic anti-tumor immunity. To this end, in Aim 1 we will phenotypically and functionally define the T cells that are present in the primary tumor microenvironment and characterize the downstream events that follow their activation. Studies proposed in Aim 2 will address the continuing hypothesis that the induction of inflammatory activity within the primary tumor will prime the development of a long-term systemic anti-tumor T-cell response that effectively infiltrates and suppresses metastatic tumors. Preliminary observations suggest that a systemic NKT/NK cell response is also involved in the suppression of metastatic tumors. In Aim 3 we will test the notion that activation of a systemic but transient NKT/NK response accompanies the early local immune events and that co-induction of innate and adaptive immunity is critical to effective eradication of systemic disease. Finally, in Aim 4 we will test the hypothesis that the intensity of the immediate effector memory T-cell response that is induced within the primary tumor microenvironment determines the efficacy of long-term cure in individual mice. The information derived from these studies is expected to provide valuable insights for the design of an effective, cytokine-based immunotherapeutic strategy for the treatment of cancer patients.