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

描述（由申请人提供）：癌症疫苗和过继性T细胞转移方法有望用于癌症治疗和预防肿瘤复发。尽管这些疗法通常增加肿瘤特异性T细胞水平，但它们通常在诱导有效的效应T细胞和可介导长期肿瘤抑制的长寿命功能性记忆T细胞方面无效。这种肿瘤特异性记忆T细胞的无效产生可能是由于缺乏来自先天免疫细胞的炎症介质的刺激。I型干扰素，包括IFN-？，是由病原体衍生的分子诱导的炎症介质，并激活先天性和适应性免疫细胞，包括CD 8 T细胞。我们在一个独特的模型系统中的初步结果表明，IFN-β的全身水平，类似于在急性病毒感染期间发现的那些，大大增强了具有抗黑素瘤活性的gp 100特异性效应和记忆CD 8 T细胞的疫苗接种诱导的产生。此外，我们的初步数据表明，IFN-？在T细胞应答的不同阶段通过多种机制发挥这种活性。我们的长期目标是了解肿瘤特异性记忆CD 8 T细胞的生成和维持的调节，并学会增强它们。该提案是对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，并将重点关注整个免疫反应中的信号，这些信号最终导致治疗性肿瘤特异性记忆CD 8 T细胞的产生和长期维持。这项建议的总体目标是了解如何干扰素-？通过其对T细胞和宿主环境的作用的机制分析促进抗肿瘤CD 8 T细胞应答。我们的中心假设是，IFN-？通过在早期致敏/扩增阶段对T细胞的直接作用和通过在随后的记忆T细胞分化和维持期间宿主来源的IL-15和CD 27/CD 70信号，增强体内和离体长寿命的肿瘤特异性记忆CD 8 T细胞的产生。这一假设将进行测试，追求以下三个具体目标：1）确定IFN-？在疫苗接种的不同阶段/IFN-？-诱导的肿瘤特异性CD 8 T细胞应答; 2）确定IFN-？诱导体内肿瘤特异性记忆性CD 8 T细胞的产生; 3）确定IFN-？可以促进肿瘤特异性CD 8 T细胞的离体产生，所述肿瘤特异性CD 8 T细胞具有体内治疗性抗肿瘤记忆T细胞的特征。总之，拟议的研究将阐明IFN-γ的潜在机制。诱导抗肿瘤免疫，并将直接导致更有效的癌症疗法的发展。

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.