Smyth Mark J, Swann Jeremy, Kelly Janice M, Cretney Erika, Yokoyama Wayne M, Diefenbach Andreas, Sayers Thomas J, Hayakawa Yoshihiro
Cancer Immunology Program, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St., 8006, Victoria, Australia.
J Exp Med. 2004 Nov 15;200(10):1325-35. doi: 10.1084/jem.20041522.
Single and combination cytokines offer promise in some patients with advanced cancer. Many spontaneous and experimental cancers naturally express ligands for the lectin-like type-2 transmembrane stimulatory NKG2D immunoreceptor; however, the role this tumor recognition pathway plays in immunotherapy has not been explored to date. Here, we show that natural expression of NKG2D ligands on tumors provides an effective target for some cytokine-stimulated NK cells to recognize and suppress tumor metastases. In particular, interleukin (IL)-2 or IL-12 suppressed tumor metastases largely via NKG2D ligand recognition and perforin-mediated cytotoxicity. By contrast, IL-18 required tumor sensitivity to Fas ligand (FasL) and surprisingly did not depend on the NKG2D-NKG2D ligand pathway. A combination of IL-2 and IL-18 stimulated both perforin and FasL effector mechanisms with very potent effects. Cytokines that stimulated perforin-mediated cytotoxicity appeared relatively more effective against tumor metastases expressing NKG2D ligands. These findings indicate that a rational choice of cytokines can be made given the known sensitivity of tumor cells to perforin, FasL, and tumor necrosis factor-related apoptosis-inducing ligand and the NKG2D ligand status of tumor metastases.
单一及联合细胞因子对一些晚期癌症患者具有潜在治疗价值。许多自发和实验性癌症天然表达凝集素样2型跨膜刺激型NKG2D免疫受体的配体；然而，这一肿瘤识别途径在免疫治疗中的作用迄今尚未得到探索。在此，我们表明肿瘤上NKG2D配体的天然表达为一些细胞因子刺激的自然杀伤（NK）细胞识别和抑制肿瘤转移提供了一个有效靶点。具体而言，白细胞介素（IL）-2或IL-12主要通过NKG2D配体识别和穿孔素介导的细胞毒性抑制肿瘤转移。相比之下，IL-18需要肿瘤对Fas配体（FasL）敏感，且令人惊讶的是不依赖于NKG2D-NKG2D配体途径。IL-2和IL-18联合刺激了穿孔素和FasL效应机制，具有非常强大的效果。刺激穿孔素介导的细胞毒性的细胞因子对表达NKG2D配体的肿瘤转移似乎相对更有效。这些发现表明，鉴于已知肿瘤细胞对穿孔素、FasL和肿瘤坏死因子相关凋亡诱导配体的敏感性以及肿瘤转移的NKG2D配体状态，可以合理选择细胞因子。
