Targeting Early Activated T cells for Adoptive Therapy

有效的抗肿瘤免疫需要产生和持续产生功能性的、高亲和力的肿瘤特异性效应细胞和记忆性T细胞。通常控制这种反应的关键因素是相关效应T细胞的激活/分化状态。我们发现，在体外启动过程中，IL-12的调节能够促进抗原特异性T细胞获得类似中央记忆的表型。这些早期激活的T(TEA)细胞的特征是淋巴结归巢受体(LN)的表达增加，体外增殖旺盛，生存时间延长，体内抗肿瘤活性增强。我们最近还观察到，环磷酰胺(CTX)预适应在回弹期诱导未成熟DC的扩张，这与体内高效的抗肿瘤反应有关。为了利用这些观察的联合潜力，我们假设，IL-12预调节的TEA细胞的生存和功能增强，当与循环中DC的频率激增相结合时，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预适应如何增强T细胞的存活和功能(观察共刺激信号、存活信号和对功能亲和力的影响)，并定义茶细胞对富含DC的环境中抗原提呈的反应(具体观察次级淋巴间隔的贡献)。理解和利用早期激活的T细胞生成和强大的循环DC诱导的组合潜力可以在体内协同增强有效的抗肿瘤反应。两年的ARRA资助机制将使我们能够通过确定IL-12调节如何增强抗原经历过的T细胞的生存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.