Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
RGS Consulting, 118 Jeremy Hill Road Pelham, Pelham, NH 03076, USA.
Int J Mol Sci. 2020 Jul 18;21(14):5085. doi: 10.3390/ijms21145085.
Invariant natural killer T (iNKT) cells are innate-like T lymphocytes characterized by the expression of an invariant T cell receptor (iTCR) that recognizes glycolipid antigens presented by the MHC I-like CD1d molecule. Following antigenic stimulation, iNKT cells rapidly produce large amounts of cytokines that can trans-activate dendritic cells (DC) and promote the anti-tumor functions of cytotoxic lymphocytes, such as natural killer (NK) and CD8 T cells. Additionally, iNKT cells can mediate robust and direct cytotoxicity against CD1d tumor targets. However, many tumors down-regulate CD1d and evade iNKT cell attack. To circumvent this critical barrier to iNKT cell anti-tumor activity, a novel monoclonal antibody (mAb), NKT14 has been recently developed. This agonistic antibody binds directly and specifically to the iTCR of murine iNKT cells. In the current study, we demonstrate that NKT14m mediates robust activation, cytokine production and degranulation of murine iNKT cells, in vitro. Consistently, NKT14m also promoted iNKT cell activation and immunomodulatory functions, in vivo. Finally, administration of NKT14m with low dose interleukin (IL)-12 further augmented iNKT cell IFN-γ production in vivo, and this combination conferred superior suppression of tumor cell growth compared to NKT14m or IL-12 alone. Together, these data demonstrate that a combination treatment consisting of low dose IL-12 and iTCR-specific mAb may be an attractive alternative to activate iNKT cell anti-tumor functions.
不变自然杀伤 T(iNKT)细胞是一种先天样 T 淋巴细胞，其特征是表达识别由 MHC I 样 CD1d 分子呈递的糖脂抗原的不变 T 细胞受体(iTCR)。在抗原刺激后，iNKT 细胞迅速产生大量细胞因子，可转激活树突状细胞(DC)，并促进细胞毒性淋巴细胞(如自然杀伤(NK)和 CD8 T 细胞)的抗肿瘤功能。此外，iNKT 细胞可以介导针对 CD1d 肿瘤靶标的强大和直接的细胞毒性。然而，许多肿瘤下调 CD1d 并逃避 iNKT 细胞攻击。为了规避 iNKT 细胞抗肿瘤活性的这一关键障碍，最近开发了一种新型单克隆抗体(mAb)，即 NKT14。这种激动性抗体直接特异性地结合到鼠 iNKT 细胞的 iTCR 上。在当前研究中，我们证明 NKT14m 在体外强烈激活、产生细胞因子并脱颗粒鼠 iNKT 细胞。一致地，NKT14m 还促进了体内 iNKT 细胞的激活和免疫调节功能。最后，用低剂量白细胞介素(IL)-12 给予 NKT14m 进一步增强了体内 iNKT 细胞 IFN-γ的产生，并且与 NKT14m 或 IL-12 单独给药相比，该组合赋予了对肿瘤细胞生长的优越抑制作用。总之，这些数据表明，由低剂量 IL-12 和 iTCR 特异性 mAb 组成的联合治疗可能是激活 iNKT 细胞抗肿瘤功能的一种有吸引力的替代方法。
