Putz Eva M, Guillerey Camille, Kos Kevin, Stannard Kimberley, Miles Kim, Delconte Rebecca B, Takeda Kazuyoshi, Nicholson Sandra E, Huntington Nicholas D, Smyth Mark J
Immunology of Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute , Herston, Queensland, Australia.
Immunology of Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; School of Medicine, The University of Queensland, Herston, Queensland, Australia.
Oncoimmunology. 2017 Feb 7;6(2):e1267892. doi: 10.1080/2162402X.2016.1267892. eCollection 2017.
The cytokine-induced SH2-containing protein CIS belongs to the suppressor of cytokine signaling (SOCS) protein family. Here, we show the critical role of CIS in suppressing natural killer (NK) cell control of tumor initiation and metastasis. -deficient mice were highly resistant to methylcholanthrene-induced sarcoma formation and protected from lung metastasis of B16F10 melanoma and RM-1 prostate carcinoma cells. In contrast, the growth of primary subcutaneous tumors, including those expressing the foreign antigen OVA, was unchanged in -deficient mice. The combination of deficiency and relevant targeted and immuno-therapies such as combined BRAF and MEK inhibitors, immune checkpoint blockade antibodies, IL-2 and type I interferon revealed further improved control of metastasis. The data clearly indicate that targeting CIS promotes NK cell antitumor functions and CIS holds great promise as a novel target in NK cell immunotherapy.
细胞因子诱导的含SH2蛋白CIS属于细胞因子信号转导抑制因子（SOCS）蛋白家族。在此，我们展示了CIS在抑制自然杀伤（NK）细胞对肿瘤起始和转移的控制中的关键作用。CIS缺陷小鼠对甲基胆蒽诱导的肉瘤形成具有高度抗性，并能免受B16F10黑色素瘤和RM-1前列腺癌细胞的肺转移。相比之下，原发性皮下肿瘤（包括那些表达外源抗原OVA的肿瘤）的生长在CIS缺陷小鼠中没有变化。CIS缺陷与相关的靶向和免疫疗法（如联合BRAF和MEK抑制剂、免疫检查点阻断抗体、IL-2和I型干扰素）相结合，显示出对转移的控制进一步改善。数据清楚地表明，靶向CIS可促进NK细胞的抗肿瘤功能，CIS作为NK细胞免疫疗法的新靶点具有很大的前景。
