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Diverse Anti-Tumor Immune Potential Driven by Individual IFNα Subtypes

单个 ifn α 亚型驱动的多样化抗肿瘤免疫潜能

  • 影响因子:4.7160
  • DOI:10.3389/fimmu.2020.00542
  • 作者列表:"Anthony C. Buzzai","Teagan Wagner","Katherine M. Audsley","Hannah V. Newnes","Lucy W. Barrett","Samantha Barnes","Ben C. Wylie","Shane Stone","Alison McDonnell","Alison McDonnell","Vanessa S. Fear","Bree Foley","Jason Waithman
  • 发表时间:2020-04-03
Abstract

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 IFNα, which all signal through a common receptor. Despite reported differences in anti-viral potencies, the concept that distinct IFNα subtypes can improve anti-cancer treatments remains unclear. We tested whether expression of unique IFNα subtypes confined to the tumor microenvironment enhances tumor control. This was systematically evaluated by transplantation of B16 murine melanoma cells secreting five unique IFNα subtypes (B16_IFNα2; B16_IFNα4; B16_IFNα5; B16_IFNα6; B16_IFNα9) into a pre-clinical murine model. We show that IFNα2 and IFNα9 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 IFNα9 delays tumor growth significantly and improves survival, whereas no enhanced survival was observed using T cells secreting IFNα4. Overall, our data shows that the expression of distinct IFNα subtypes within the tumor microenvironment results in different anti-tumor activities, and differentially affects the efficacy of a cancer therapy targeting established disease.

摘要

利用 T 细胞免疫的免疫疗法在治疗癌症方面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获益。肿瘤微环境中 I 型干扰素 (IFN) 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 种不同亚型的 ifn α,它们都通过一个共同的受体发出信号。尽管报道的抗病毒效力存在差异,但不同的 ifn α 亚型可以改善抗癌治疗的概念仍不清楚。我们检测了局限于肿瘤微环境的独特 ifn α 亚型的表达是否增强了肿瘤控制。通过将分泌 5 种独特 ifn α 亚型 (b16_ifn α 2; B16_ifn α 4; B16_ifn α 5; B16_ifn α 6; B16_ifn α 9) 的 B16 鼠黑色素瘤细胞移植到临床前鼠模型中进行系统评价。我们发现 ifn α 2 和 ifn α 9 是唯一能够完全控制肿瘤生长的亚型,这种保护作用依赖于适应性免疫反应的存在。我们接下来确定这些差异是否扩展到其他模型系统,并发现工程分泌 ifn α 9 的肿瘤特异性 CD8 + T 细胞的过继转移显著延缓肿瘤生长并提高生存率,而使用分泌 ifn α 4 的 T 细胞未观察到生存率增强。总体而言,我们的数据显示,肿瘤微环境内不同 ifn α 亚型的表达导致不同的抗肿瘤活性,并差异影响靶向已确定疾病的癌症治疗的疗效。

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