Swann Jeremy B, Hayakawa Yoshihiro, Zerafa Nadeen, Sheehan Kathleen C F, Scott Bernadette, Schreiber Robert D, Hertzog Paul, Smyth Mark J
Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 8006 Victoria, Australia.
J Immunol. 2007 Jun 15;178(12):7540-9. doi: 10.4049/jimmunol.178.12.7540.
This study demonstrates that type I IFNs are an early and critical regulator of NK cell numbers, activation, and antitumor activity. Using both IFNAR1- and IFNAR2-deficient mice, as well as an IFNAR1-blocking Ab, we demonstrate that endogenous type I IFN is critical for controlling NK cell-mediated antitumor responses in many experimental tumor models, including protection from methylcholanthrene-induced sarcomas, resistance to the NK cell-sensitive RMA-S tumor and cytokine immunotherapy of lung metastases. Protection from RMA-S afforded by endogenous type I IFN is more potent than that of other effector molecules such as IFN-gamma, IL-12, IL-18, and perforin. Furthermore, cytokine immunotherapy using IL-12, IL-18, or IL-21 was effective in the absence of endogenous type I IFN, however the antimetastatic activity of IL-2 was abrogated in IFNAR-deficient mice, primarily due to a defect in IL-2-induced cytotoxic activity. This study demonstrates that endogenous type I IFN is a central mediator of NK cell antitumor responses.
本研究表明，I型干扰素是自然杀伤（NK）细胞数量、活化及抗肿瘤活性的早期关键调节因子。利用干扰素α/β受体1（IFNAR1）和干扰素α/β受体2（IFNAR2）缺陷小鼠以及一种IFNAR1阻断抗体，我们证明内源性I型干扰素在许多实验性肿瘤模型中对控制NK细胞介导的抗肿瘤反应至关重要，包括预防甲基胆蒽诱导的肉瘤、对NK细胞敏感的RMA-S肿瘤的抗性以及肺转移瘤的细胞因子免疫治疗。内源性I型干扰素对RMA-S的保护作用比其他效应分子如干扰素γ、白细胞介素-12（IL-12）、白细胞介素-18（IL-18）和穿孔素更强。此外，在缺乏内源性I型干扰素的情况下，使用IL-12、IL-18或IL-21进行细胞因子免疫治疗是有效的，然而，IL-2的抗转移活性在IFNAR缺陷小鼠中被消除，主要是由于IL-诱导的细胞毒活性存在缺陷。本研究表明，内源性I型干扰素是NK细胞抗肿瘤反应的核心介质。
