IL15 Stimulation with TIGIT Blockade Reverses CD155-mediated NK-Cell Dysfunction in Melanoma.
IL15 Stimulation with TIGIT Blockade Reverses CD155-mediated NK-Cell Dysfunction in Melanoma.
复制标题
DOI：
10.1158/1078-0432.ccr-20-0575
复制
发表时间：
2020-10-15
期刊：
影响因子：
--
通讯作者：
Zarour HM
中科院分区：
文献类型：
--
作者：
Chauvin JM;Ka M;Pagliano O;Menna C;Ding Q;DeBlasio R;Sanders C;Hou J;Li XY;Ferrone S;Davar D;Kirkwood JM;Johnston RJ;Korman AJ;Smyth MJ;Zarour HM
自然杀伤(NK)细胞在肿瘤免疫监控中发挥着重要作用。多种激活和抑制受体调节NK细胞介导的肿瘤控制。抑制性受体TIGIT及其反式受体CD226对NK细胞介导的肿瘤反应性具有相反的作用。我们用多参数流式细胞术检测了新鲜分离自健康献血者和黑色素瘤患者的NK细胞的频率、表型和功能。我们评估了TIGIT和CD226与CD155结合后细胞表面的表达和内化。我们在体外和两种小鼠模型中评价了IL-15和TIGIT阻断在增加NK细胞介导的细胞毒作用中的作用。NK细胞在转移性黑色素瘤中出现频率较低，功能失调，并下调TIGIT和CD226的表达。与TIGIT−NK细胞相比，TIGIT+NK细胞对CD155+MHCI类缺陷黑色素瘤细胞具有更高的杀伤能力和成熟能力，但却相反地降低了对CD155+MHCI类缺陷细胞的杀伤活性。膜结合的CD155触发CD226的内化和降解，导致NK细胞介导的肿瘤反应性降低。IL-15通过肿瘤浸润性NK细胞(TINK)增加TIGIT和CD226基因的表达，并与TIGIT阻断一起，在体外增强NK细胞介导的黑色素瘤细胞毒作用，并减少两种黑色素瘤模型的肿瘤转移。TIGIT的特异性缺失增强了IL-15的抗转移活性，而CD226阻断则减弱了IL-15和TIGIT的作用。我们的发现支持了用IL-15和TIGIT阻断的新型联合免疫疗法的发展，以促进NK细胞介导的MHC I类缺陷黑色素瘤的破坏，这种黑色素瘤对CD8+T细胞介导的免疫无效。
Natural Killer (NK) cells play a critical role in tumor immunosurveillance. Multiple activating and inhibitory receptors regulate NK cell-mediated tumor control. The inhibitory receptor TIGIT and its counter-receptor CD226 exert opposite effects on NK cell-mediated tumor reactivity. We evaluated the frequency, phenotype and functions of NK cells freshly isolated from healthy donors and melanoma patients with multiparameter flow cytometry. We assessed TIGIT and CD226 cell surface expression and internalization upon binding to CD155. We evaluated the role of Interleukin (IL)-15 and TIGIT blockade in increasing NK cell-mediated cytotoxicity in vitro and in two mouse models. NK cells are present at low frequencies in metastatic melanoma, are dysfunctional and downregulate both TIGIT and CD226 expression. As compared with TIGIT− NK cells, TIGIT+ NK cells exhibit higher cytotoxic capacity and maturation but paradoxically lower cytotoxicity against CD155+ MHC class I-deficient melanoma cells. Membrane-bound CD155 triggers CD226 internalization and degradation, resulting in decreased NK cell-mediated tumor reactivity. IL-15 increases TIGIT and CD226 gene expression by tumor-infiltrating NK cells (TiNKs) and, together with TIGIT blockade, increases NK cell-mediated melanoma cytotoxicity in vitro and decreases tumor metastasis in two mouse melanoma models. Specific deletion of TIGIT on transferred NK cells enhances the anti-metastatic activity of IL-15, while CD226 blockade decreases the effects of IL-15 and TIGIT blockade. Our findings support the development of novel combinatorial immunotherapy with IL-15 and TIGIT blockade to promote NK cell-mediated destruction of MHC class I-deficient melanoma, which are refractory to CD8+ T cell-mediated immunity.