Integrating Innate & Adaptive Immunity in Cancer Therapy

描述（申请人提供）：IL-12和GM-CSF从生物可降解微球缓慢释放到单个原发性肿瘤结节中，促进了转移性鼠肿瘤模型中强效全身抗肿瘤免疫的发展和播散性肿瘤结节的完全根除。在该模型中，尚未确定介导系统性疾病根除的免疫机制。我们的假设是，IL-12和GM-CSF局部和持续释放到肿瘤微环境中促进肿瘤相关效应记忆T细胞的活化，然后启动局部炎症事件的级联反应，导致系统性抗肿瘤免疫的发展。为此，在目标1中，我们将在表型和功能上定义存在于原发性肿瘤微环境中的T细胞，并表征其激活后的下游事件。目标2中提出的研究将解决以下持续假设：原发性肿瘤内炎症活性的诱导将引发长期全身性抗肿瘤T细胞应答的发展，有效浸润和抑制转移性肿瘤。 初步观察表明，全身NKT/NK细胞反应也参与了转移性肿瘤的抑制。在目标3中，我们将测试这样的概念，即全身性但短暂的NKT/NK应答的激活伴随着早期局部免疫事件，并且先天性和适应性免疫的共诱导对于有效根除全身性疾病至关重要。最后，在目标4中，我们将检验以下假设：在原发性肿瘤微环境中诱导的即时效应记忆T细胞应答的强度决定了个体小鼠长期治愈的疗效。从这些研究中获得的信息预计将为设计用于治疗癌症患者的有效的基于精氨酸的免疫策略提供有价值的见解。

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.