Integrating Innate & Adaptive Immunity in Cancer Therapy

描述（由申请人提供）：在转移性小鼠肿瘤模型中，从可生物降解的微球中缓慢释放IL-12和GM-CSF到单个原发肿瘤结节中，促进了强效全身抗肿瘤免疫的发展和完全根除播散性肿瘤结节。在这个模型中，介导系统性疾病根除的免疫机制尚未被定义。我们的假设是，IL-12和GM-CSF在肿瘤微环境中的局部持续释放促进了肿瘤相关效应记忆t细胞的激活，然后启动一系列局部炎症事件，导致系统性抗肿瘤免疫的发展。为此，在Aim 1中，我们将从表型和功能上定义原发肿瘤微环境中存在的T细胞，并描述它们激活后的下游事件。Aim 2中提出的研究将解决一个持续的假设，即在原发肿瘤内诱导炎症活动将启动长期系统性抗肿瘤t细胞反应的发展，该反应有效地浸润和抑制转移性肿瘤。

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.