Diverse Anti-Tumor Immune Potential Driven by Individual IFNα Subtypes
Diverse Anti-Tumor Immune Potential Driven by Individual IFNα Subtypes
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DOI：
10.3389/fimmu.2020.00542
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发表时间：
2020-04-03
影响因子：
7.3
通讯作者：
Waithman, Jason
中科院分区：
文献类型：
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作者：
Buzzai, Anthony C.;Wagner, Teagan;Waithman, Jason
利用T细胞免疫的免疫疗法在治疗癌症方面已显示出显著的临床成功。然而，只有一部分患者从这些治疗中受益。I型干扰素在肿瘤微环境中的存在对于驱动有效的肿瘤特异性T细胞免疫至关重要。个体可以产生12种不同的干扰素α亚型，所有这些亚型都通过共同的受体发出信号。尽管据报道，在抗病毒效力方面存在差异，但不同的干扰素α亚型可以改善抗癌治疗的概念仍不清楚。我们测试了仅限于肿瘤微环境的独特干扰素α亚型的表达是否增强了肿瘤控制。通过将分泌5种独特的干扰素α亚型(B16_干扰素α2；B16_干扰素α4；B16_干扰素α5；B16_干扰素α6；B16_干扰素α9)的B16小鼠黑色素瘤细胞移植到临床前小鼠模型中进行了系统的评估。我们发现干扰素α2和干扰素α9是唯一能够完全控制肿瘤生长的亚型，这种保护依赖于适应性免疫反应的存在。接下来，我们确定这些差异是否延伸到其他模型系统，并发现过继转移肿瘤特异性CD8(+)T细胞以分泌干扰素α9显著延缓肿瘤生长并提高存活率，而使用分泌干扰素α4的T细胞则没有观察到提高存活率。总体而言，我们的数据表明，肿瘤微环境中不同的干扰素亚型的表达导致不同的抗肿瘤活性，并不同地影响针对既定疾病的癌症治疗的疗效。
Immunotherapies harnessing T cell immunity have shown remarkable clinical success for the management of cancer. However, only a proportion of patients benefit from these treatments. The presence of type I interferon (IFN) within the tumor microenvironment is critical for driving effective tumor-specific T cell immunity. Individuals can produce 12 distinct subtypes of IFN alpha, which all signal through a common receptor. Despite reported differences in anti-viral potencies, the concept that distinct IFN alpha subtypes can improve anti-cancer treatments remains unclear. We tested whether expression of unique IFN alpha subtypes confined to the tumor microenvironment enhances tumor control. This was systematically evaluated by transplantation of B16 murine melanoma cells secreting five unique IFN alpha subtypes (B16_IFN alpha 2; B16_IFN alpha 4; B16_IFN alpha 5; B16_IFN alpha 6; B16_IFN alpha 9) into a pre-clinical murine model. We show that IFN alpha 2 and IFN alpha 9 are the only subtypes capable of completely controlling tumor outgrowth, with this protection dependent on the presence of an adaptive immune response. We next determined whether these differences extended to other model systems and found that the adoptive transfer of tumor-specific CD8(+) T cells engineered to secrete IFN alpha 9 delays tumor growth significantly and improves survival, whereas no enhanced survival was observed using T cells secreting IFN alpha 4. Overall, our data shows that the expression of distinct IFN alpha subtypes within the tumor microenvironment results in different anti-tumor activities, and differentially affects the efficacy of a cancer therapy targeting established disease.