IL-15 Deficient Tax Mice Reveal a Role for IL-1α in Tumor Immunity

IL-15 is recognized as a promising candidate for tumor immunotherapy and has been described as both a promoter of cancer and a promoter of anti-cancer immunity. IL-15 was discovered in cells transformed by HTLV-1, the etiologic agent of adult T cell leukemia/lymphoma (ATL) and the human retrovirus that carries the Tax oncogene. We have developed the TAX-LUC mouse model of ATL in which Tax expression drives both malignant transformation and luciferase expression, enabling non-invasive imaging of tumorigenesis in real time. To identify the role of IL-15 in spontaneous development of lymphoma in vivo, an IL-15−/− TAX-LUC strain was developed and examined. The absence of IL-15 resulted in aggressive tumor growth and accelerated mortality and demonstrated that IL-15 was not required for Tax-mediated lymphoma but was essential for anti-tumor immunity. Further analysis revealed a unique transcriptional profile in tumor cells that arise in the absence of IL-15 that included a significant increase in the expression of IL-1α and IL-1α-regulated cytokines. Moreover, anti-IL-1α antibodies and an IL-1 receptor antagonist (Anakinra) were used to interrogate the potential of IL-1α targeted therapies in this model. Taken together, these findings identify IL-15 and IL-1α as therapeutic targets in lymphoma.

白介素-15（IL-15）被视作肿瘤免疫治疗极具潜力的候选靶点，同时被报道兼具促癌与激活机体抗癌免疫的双重功能。白介素-15最初在被人类T淋巴细胞病毒I型（HTLV-1）转化的细胞中被发现，该病毒是成人T细胞白血病/淋巴瘤（ATL）的致病原，同时是携带Tax癌基因的人类逆转录病毒。本研究构建了ATL的TAX-LUC小鼠模型，该模型中Tax的表达可同时驱动恶性转化与荧光素酶表达，从而实现肿瘤发生过程的实时无创成像。为明确IL-15在体内淋巴瘤自发形成过程中的作用，我们构建了IL-15基因敲除的TAX-LUC小鼠品系并开展了相关验证实验。实验结果显示，IL-15的缺失会导致肿瘤侵袭性生长加快，并缩短小鼠的存活时长；同时证实，IL-15并非Tax介导的淋巴瘤发生所必需，但却是机体抗肿瘤免疫功能不可或缺的关键因子。进一步的转录组分析显示，在IL-15缺失的微环境中产生的肿瘤细胞具备独特的转录谱特征，其中白介素-1α（IL-1α）及其调控的细胞因子的表达水平显著上调。此外，本研究通过抗IL-1α抗体与IL-1受体拮抗剂阿那白滞素（Anakinra），探究了靶向IL-1α的治疗策略在该模型中的应用潜力。综上，本研究结果证实，IL-15与IL-1α均可作为淋巴瘤的治疗靶点。