Promoting the generation of long-lived, anti-tumor memory T cells with IFN-alpha

描述(由申请人提供)：癌症疫苗和采用的T细胞转移方法为癌症治疗和预防肿瘤复发提供了希望。虽然这些疗法通常会提高肿瘤特异性T细胞水平，但它们在诱导强大的效应性T细胞和能够介导长期肿瘤抑制的长期功能记忆T细胞方面往往无效。这种无效的肿瘤特异性记忆T细胞的产生可能是由于缺乏来自天然免疫细胞的炎性介质的刺激。I型干扰素，包括干扰素-β，是由病原体分子诱导的炎症介质，能激活包括CD8T细胞在内的天然免疫细胞和获得性免疫细胞。我们在一个独特的模型系统中的初步结果表明，系统中与急性病毒感染时发现的水平相似的干扰素-β，极大地增强了疫苗诱导的具有抗黑色素瘤活性的gp100特异性效应和记忆性CD8T细胞的产生。此外，我们的初步数据显示，干扰素-？在T细胞反应的不同阶段通过多种机制发挥这种作用。我们的长期目标是了解肿瘤特异性记忆CD8T细胞的产生和维持的调节，并学习增强它们。这项建议是对NIH计划公告PA-07-255“癌症免疫学中的记忆T淋巴细胞”的直接回应，并将重点放在整个免疫反应中的信号，最终导致治疗性肿瘤特异性记忆CD8 T细胞的产生和长期维持。这项建议的总体目标是了解干扰素-？通过机械解剖其对T细胞和宿主环境的影响来促进抗肿瘤CD8 T细胞的反应。我们的中心假设是干扰素？通过在早期启动/扩增阶段直接作用于T细胞，以及在随后的记忆T细胞分化和维持期间通过宿主衍生的IL-15和CD27/CD70信号，增强体内和体外长寿命、肿瘤特异性记忆CD8 T细胞的生成。这一假说将通过追求以下三个具体目标来检验：1)确定干扰素-？在疫苗接种的不同阶段，干扰素诱导的肿瘤特异性CD8T细胞反应；2)确定干扰素诱导体内产生肿瘤特异性记忆性CD8T细胞的分子机制；可促进肿瘤特异性CD8T细胞的体外生成，在体内具有治疗性抗肿瘤记忆T细胞的特性。总体而言，拟议的研究将阐明干扰素？诱导抗肿瘤免疫的潜在机制，并将直接导致更有效的癌症治疗方法的开发。

DESCRIPTION (provided by applicant): Cancer vaccines and adoptive T cell transfer approaches hold promise for cancer treatment and the prevention of tumor recurrence. Whereas these therapies often increase tumor-specific T cell levels, they are often ineffective in inducing potent effector T cells and long-lived, functional memory T cells that can mediate long-term tumor suppression. This ineffective generation of tumor-specific memory T cells is possibly due to a lack of stimulation by inflammatory mediators derived from innate immune cells. Type I Interferons, including IFN-?, are inflammatory mediators induced by pathogen-derived molecules and activate innate and adaptive immune cells including CD8 T cells. Our preliminary results in a unique model system demonstrate that systemic levels of IFN-?, similar to those found during acute viral infection, greatly enhance the vaccination-induced generation of gp100-specific effector and memory CD8 T cells with anti- melanoma activity. In addition, our preliminary data show that IFN-? exerts this activity through multiple mechanisms during distinct phases of the T cell response. Our long-term goals are to understand the regulation of generation and maintenance of tumor-specific memory CD8 T cells and learn to enhance them. This proposal is in direct response to the NIH Program Announcement PA-07-255 "Memory T lymphocytes in Cancer Immunology" and will focus on signals throughout the immune response that culminate into the generation and long-term maintenance of therapeutic tumor-specific memory CD8 T cells. The overall objective of this proposal is to understand how IFN-? promotes anti-tumor CD8 T cell responses through mechanistic dissection of its effects on T cells and the host environment. Our central hypothesis is that IFN-? enhances the in vivo and ex vivo generation of long-lived, tumor-specific memory CD8 T cells through direct effects on T cells during the early priming/expansion phase and through host-derived IL-15 and CD27/CD70 signals during subsequent memory T cell differentiation and maintenance. This hypothesis will be tested by pursuing the following three specific aims: 1) Determine the contribution of IFN-? during the different phases of the vaccination/IFN-?-induced, tumor-specific CD8 T cell response; 2) Identify the molecular mechanisms underlying the IFN-?-induced in vivo generation of tumor-specific memory CD8 T cells; 3) Determine whether IFN-? can promote the ex vivo generation of tumor-specific CD8 T cells that have characteristics of therapeutic anti-tumor memory T cells in vivo. Overall, the proposed studies will elucidate the mechanisms underlying IFN-?-induced anti-tumor immunity and will directly lead to the development of more effective cancer therapies.