Targeting Early Activated T cells for Adoptive Therapy

有效的抗肿瘤免疫需要功能性的、高活性的肿瘤特异性效应细胞和记忆T细胞的产生和持续存在。通常控制这种反应的关键因素之一是相关效应t细胞的激活/分化状态。我们观察到IL- 12在体外启动过程中能够促进抗原特异性T细胞获得中枢记忆（Tcm）样表型。这些“早期激活”的T （TEA）细胞的特点是淋巴结（LN）归巢受体的表达增加，体外增殖强劲，生存期延长，体内抗肿瘤活性增强。我们最近还观察到，环磷酰胺（CTX）预处理诱导未成熟dc在反弹期主要在外周血中扩张，这与体内高度有效的抗肿瘤反应有关。为了利用这些观察结果的综合潜力，我们假设IL- 12预调节TEA细胞的存活率和功能的增强，与循环dc频率的增加相结合，将导致产生更有效的抗肿瘤免疫。为了验证这一假设，我们建议定义IL-12预处理如何增强t细胞的存活和功能（研究共刺激信号、生存信号和对功能亲和度的影响），并定义在DC丰富的环境中TEA细胞对抗原呈递的反应（特别是研究次级淋巴细胞室的贡献）。理解和利用早期激活T细胞生成和强大循环DC诱导的联合潜力的能力可以协同增强体内有效抗肿瘤反应的产生。为期两年的ARRA资助机制将使我们能够通过定义IL-12调节如何增强抗原经历的t细胞存活和功能来解决这一目标的第一个方面。

Effective anti-tumor immunity requires the generation and persistence of functional, high avidity tumor-specific effector and memory T cells. Among the critical factors that often control this response is the activation/differentiation state of the relevant effector T-cells. We have made the singular observation that IL- 12 conditioning during in vitro priming is able to promote the acquisition of a central memory (Tcm) like phenotype in antigen-specific T cells. These “early activated” T (TEA) cells are characterized by increased expression of lymph node (LN) homing receptors, robust proliferation in vitro, an augmented survival, and increased anti-tumor activity in vivo. We have also recently observed that cyclophosphamide (CTX) preconditioning induces expansion of immature DCs mainly in the peripheral blood during the rebound phase which is associated with highly effective anti-tumor responses in vivo. With an interest in capitalizing on the combined potential of these observations, we hypothesize that the enhanced survival and function of IL- 12 pre-conditioned TEA cells will result in the generation of more effective anti-tumor immunity when combined with a surging frequency of circulating DCs. To test this hypothesis we propose to define how IL-12 pre-conditioning enhances T-cell survival and function (looking at co-stimulation signature, survival signaling, and impact on functional avidity) and define the TEA cell response to antigen presentation in a DC rich environment (looking specifically at the contribution of secondary lymphoid compartments. The ability to understand and harness the combined potential of early activated T cell generation and robust circulating DC induction could serve to synergistically augment in the generation of an effective anti-tumor response in vivo. The two year ARRA funding mechanism will allow us to address the first aspect of this goal by defining how IL-12 conditioning enhances antigen experienced T-cell survival and function.