CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：IL15/IL15Rα complex induces an anti-tumor immune response following radiation therapy only in the absence of Tregs and fails to induce expansion of progenitor TCF1+ CD8 T cells.
IL15/IL15Rα complex induces an anti-tumor immune response following radiation therapy only in the absence of Tregs and fails to induce expansion of progenitor TCF1+ CD8 T cells.
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我们的结果说明了一种机制，即通过 IL2Rβ信号传导实现效应 T 细胞不受阻碍的激活以及 Treg 抑制，是介导抗肿瘤免疫应答所必需的。
本研究旨在探究包含IL15的治疗方案是否能改善对放疗的反应，并揭示使用新型治疗组合克服IL15激动剂耐药性的机制依据。
采用PDAC原位肿瘤模型确定治疗反应。分别采用IL15-/-和Rag1-/-小鼠模型确定对IL15和CTL的依赖性。采用流式细胞术评估免疫细胞频率和活化状态。采用磷酸化蛋白质组学分析表征细胞内信号通路。
我们表明，放射治疗（RT）与IL15/IL15Ra融合复合物（称为IL15c）联合使用未能赋予抗肿瘤疗效；然而，同时给予aCD25 Treg耗竭抗体可引发CD8驱动的抗肿瘤免疫应答。利用IL15-/-和Rag1-/-小鼠，我们证明对RT + IL15c + aCD25的应答依赖于IL15和CTL。此外，尽管RT + IL15c + aCD25与RT + PD1-IL2v（一种具有PD-1和IL2Rβγ结合结构域的新型免疫细胞因子）联合治疗后的生存获益相当，但CTL免疫表型和细胞内代谢物的磷酸化蛋白质组分析显示，经RT + PD1-IL2v处理的CD8 T细胞的活化和功能显著上调。最后，我们表明，在缺乏功能性IL15信号的情况下，对RT + PD1-IL2v的免疫刺激应答显著减弱，同时伴随TCF+ CD8 T细胞生成的缺失。
This work seeks to understand whether IL15-incorporating treatments improve response to radiotherapy and uncover mechanistic rationale for overcoming resistance to IL15 agonism using novel therapeutic combinations. EXPERIMENTAL DESIGN: Orthotopic tumor models of PDAC were used to determine response to treatment. IL15-/- and Rag1-/- mouse models were employed to determine dependence on IL15 and CTLs, respectively. Flow cytometry was used to assess immune cell frequency and activation state. Phospho-proteomic analyses were used to characterize intracellular signaling pathways.
We show that the combination of radiation therapy (RT) and an IL15/IL15Ra fusion complex (denoted IL15c) fails to confer anti-tumor efficacy; however, a CD8-driven anti-tumor immune response is elicited with the concurrent administration of an aCD25 Treg-depleting antibody. Using IL15-/- and Rag1-/- mice, we demonstrate that response to RT + IL15c + aCD25 is dependent on both IL15 and CTLs. Furthermore, despite an equivalent survival benefit following treatment with RT + IL15c + aCD25 and combination RT + PD1-IL2v, a novel immunocytokine with PD-1 and IL2Rβγ binding domains, CTL immunophenotyping and phospho-proteomic analysis of intracellular metabolites showed significant upregulation of activation and functionality in CD8 T cells treated with RT + PD1-IL2v. Finally, we show the immunostimulatory response to RT + PD1-IL2v is significantly diminished with a concurrent lack of TCF+ CD8 T cell generation in the absence of functional IL15 signaling.
Our results are illustrative of a mechanism wherein unimpeded effector T cell activation through IL2Rβ signaling and Treg inhibition are necessary in mediating an anti-tumor immune response.
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