Kasamatsu Jun, Azuma Masahiro, Oshiumi Hiroyuki, Morioka Yuka, Okabe Masaru, Ebihara Takashi, Matsumoto Misako, Seya Tsukasa
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan;
Division of Disease Model Innovation, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-8638, Japan;
J Immunol. 2014 Nov 15;193(10):5199-207. doi: 10.4049/jimmunol.1400924. Epub 2014 Oct 15.
Polyinosinic-polycytidylic acid strongly promotes the antitumor activity of NK cells via TLR3/Toll/IL-1R domain-containing adaptor molecule 1 and melanoma differentiation-associated protein-5/mitochondrial antiviral signaling protein pathways. Polyinosinic-polycytidylic acid acts on accessory cells such as dendritic cells (DCs) and macrophages (Mφs) to secondarily activate NK cells. In a previous study in this context, we identified a novel NK-activating molecule, named IFN regulatory factor 3-dependent NK-activating molecule (INAM), a tetraspanin-like membrane glycoprotein (also called Fam26F). In the current study, we generated INAM-deficient mice and investigated the in vivo function of INAM. We found that cytotoxicity against NK cell-sensitive tumor cell lines was barely decreased in Inam(-/-) mice, whereas the number of IFN-γ-producing cells was markedly decreased in the early phase. Notably, deficiency of INAM in NK and accessory cells, such as CD8α(+) conventional DCs and Mφs, led to a robust decrease in IFN-γ production. In conformity with this phenotype, INAM effectively suppressed lung metastasis of B16F10 melanoma cells, which is controlled by NK1.1(+) cells and IFN-γ. These results suggest that INAM plays a critical role in NK-CD8α(+) conventional DC (and Mφ) interaction leading to IFN-γ production from NK cells in vivo. INAM could therefore be a novel target molecule for cancer immunotherapy against IFN-γ-suppressible metastasis.
聚肌苷酸-聚胞苷酸通过Toll样受体3/Toll/白细胞介素-1受体结构域含有的接头分子1和黑色素瘤分化相关蛋白5/线粒体抗病毒信号蛋白途径，强力促进自然杀伤细胞（NK细胞）的抗肿瘤活性。聚肌苷酸-聚胞苷酸作用于诸如树突状细胞（DCs）和巨噬细胞（Mφs）等辅助细胞，继而激活NK细胞。在此背景下的一项先前研究中，我们鉴定出一种新型的NK细胞激活分子，命名为干扰素调节因子3依赖性NK细胞激活分子（INAM），一种四跨膜样膜糖蛋白（也称为Fam26F）。在当前研究中，我们培育出INAM基因缺陷型小鼠，并研究了INAM的体内功能。我们发现，Inam(-/-)小鼠对NK细胞敏感肿瘤细胞系的细胞毒性几乎没有降低，而在早期阶段产生干扰素-γ的细胞数量显著减少。值得注意的是，NK细胞以及诸如CD8α(+)传统DCs和Mφs等辅助细胞中INAM的缺失，导致干扰素-γ产生大幅减少。与这种表型一致，INAM有效抑制了由NK1.1(+)细胞和干扰素-γ控制的B16F10黑色素瘤细胞的肺转移。这些结果表明，INAM在体内导致NK细胞产生干扰素-γ的NK-CD8α(+)传统DC（和Mφ）相互作用中起关键作用。因此，INAM可能是针对干扰素-γ可抑制转移的癌症免疫疗法的新型靶分子。
