Challenges of iNKT cell-based antitumor immunotherapies
Challenges of iNKT cell-based antitumor immunotherapies
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基于 iNKT 细胞的抗肿瘤免疫疗法的挑战
DOI：
10.1038/s41423-020-0479-7
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发表时间：
2020-06
影响因子：
24.1
通讯作者：
Huimin Zhang;L. Bai
中科院分区：
文献类型：
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作者：
Huimin Zhang;L. Bai
由于其功能优势和低毒性，不变的自然杀伤T（iNKT）细胞是抗肿瘤免疫治疗的良好候选者。动物模型研究和临床试验显示了其良好的应用前景。在这里，我们讨论了基于iNKT细胞的免疫疗法的策略和挑战。iNKT细胞表达一种半恒定T细胞抗原受体（TCR），其α链可变区在人体中由Vα 24 J α18编码，在小鼠中由Vα 14 J α18编码。与传统的T细胞不同，iNKT细胞表现出效应记忆表型，并识别由非多态性CD 1d分子呈递的脂质抗原。1由于专职和非专职抗原呈递细胞（APC）广泛表达CD 1d，iNKT细胞能够以相互作用的方式直接调节多种免疫细胞的功能，包括树突状细胞（DC）、B细胞和巨噬细胞。在活化后，iNKT细胞可以快速产生大量的Th 1和Th 2细胞因子，包括IFNγ、TNFα、IL 2、IL 4和IL 13，从而间接调节旁观者细胞的功能，包括自然杀伤（NK）细胞和T细胞。这些特性使得iNKT细胞成为体内重要的免疫调节细胞。此外，iNKT细胞可以通过穿孔素和颗粒酶介导的细胞毒性杀死靶细胞，类似于NK和CD 8 T细胞。iNKT细胞对肿瘤的免疫监视作用已通过小鼠和人类的研究得到证实，如iNKT细胞缺陷小鼠中肿瘤生长增加以及体内激活iNKT细胞后在临床中观察到的有益效果所示。2机制研究表明，表达CD 1d的肿瘤细胞可以通过识别脂质抗原被iNKT细胞直接杀死。对于不表达CD 1d的肿瘤细胞，iNKT细胞的激活通过反式激活NK和CD 8 T细胞以及耗尽肿瘤相关巨噬细胞来促进肿瘤清除。1这些直接和间接的肿瘤清除策略，加上由于CD 1d的非多态性，异基因细胞输注中移植物抗宿主病（GVHD）的风险较低，使iNKT细胞成为抗肿瘤免疫治疗的理想候选细胞。以往的临床研究表明，用脂质抗原α-半乳糖神经酰胺（αGalCer）或单独αGalCer脉冲的APC转移扩增的iNKT细胞和活化iNKT细胞的策略是安全可行的。有趣的是，给予α GalCer脉冲的DC比给予αGalCer更好地诱导Th 1反应，因此表现出更强的抗肿瘤作用。3虽然iNKT细胞同时释放Th 1和Th 2细胞因子，但一些αGalCer变体，如AH 10 -7和α-C-GalCer，诱导Th 1偏好的免疫应答。因此，修饰脂质抗原以偏向Th 1应答可能会增强iNKT细胞介导的抗肿瘤应答。另一方面，iNKT细胞的活化通过增强DC的成熟来促进CD 8 T细胞应答。基于iNKT细胞的佐剂活性，设计了一些新的策略，通过迫使DC、肿瘤细胞或人工APC同时呈递脂质抗原αGalCer和细胞内肿瘤抗原来增强适应性T细胞应答。2最近，嵌合抗原受体（CAR）-T细胞在免疫治疗中的应用取得了显著的治疗效果。类似的策略已用于产生CAR-iNKT细胞，这些CAR-iNKT细胞通过靶向肿瘤细胞表面抗原直接杀死肿瘤细胞。5，6使用神经节苷脂GD 2特异性CAR-iNKT细胞（NCT 02439788和NCT 03294954）和CD 19特异性CAR-iNKT细胞（NCT 03774654）的临床试验已经启动，用于...
Invariant natural killer T (iNKT) cells are good candidates for antitumor immunotherapies due to their functional advantages and low toxicity. Their promising utility has been exhibited by studies in animal models and clinical trials. Here, we discuss the strategies and challenges of iNKT cell-based immunotherapies. iNKT cells express a semi-invariant T cell antigen receptor (TCR), with an α chain variable region encoded by Vα24Jα18 in humans and Vα14Jα18 in mice. Unlike conventional T cells, iNKT cells show an effector memory phenotype and recognize lipid antigens presented by nonpolymorphic CD1d molecules. 1 Due to the broad expression of CD1d by professional and nonprofessional antigenpresenting cells (APCs), iNKT cells are able to directly regulate the function of multiple immune cells, including dendritic cells (DCs), B cells, and macrophages, in a reciprocal manner. Upon activation, iNKT cells can rapidly produce large amounts of Th1 and Th2 cytokines, including IFNγ, TNFα, IL2, IL4, and IL13, and thus indirectly modulate the function of bystander cells, including natural killer (NK) cells and T cells. These properties make iNKT cells important immunoregulatory cells in vivo. Additionally, iNKT cells can kill target cells by perforin-and granzyme-mediated cytotoxicity, similar to NK and CD8 T cells. The immunosurveillance role of iNKT cells against tumors has been demonstrated by studies in both mice and humans, as indicated by the increased tumor growth in iNKT cell-deficient mice as well as the beneficial effects seen in the clinic after activating iNKT cells in vivo. 2 Mechanistic studies revealed that CD1d-expressing tumor cells can be directly killed by iNKT cells via recognition of lipid antigens. For tumor cells without CD1d expression, activation of iNKT cells promotes tumor clearance by transactivating NK and CD8 T cells, as well as by depleting tumor-associated macrophages. 1 These direct and indirect tumor clearance strategies, in addition to the low risk of graft-versus-host disease (GVHD) in allogeneic cell infusion due to the nonpolymorphism of CD1d, make iNKT cells ideal candidates for antitumor immunotherapies. Previous clinical studies have shown that strategies transferring expanded iNKT cells and activating iNKT cells with APCs that have been pulsed with the lipid antigen α-galactosylceramide (αGalCer) or αGalCer alone are safe and feasible. Interestingly, administration of αGalCer-pulsed DCs better induces Th1 responses than αGalCer administration and thus exhibits stronger antitumor effects. 3 Although iNKT cells release both Th1 and Th2 cytokines, some αGalCer variants, such as AH10-7 and α-C-GalCer, induce Th1-biased immune responses. 1, 4 Therefore, modifying the lipid antigens to skew toward Th1 responses would presumably augment iNKT cell-mediated antitumor responses. On the other hand, activation of iNKT cells promotes CD8 T cell responses by enhancing the maturation of DCs. Based on the adjuvant activity of iNKT cells, some new strategies are designed to augment adaptive T cell responses by forcing DCs, tumor cells or artificial APCs to simultaneously present the lipid antigen αGalCer and intracellular tumor antigens. 2 Recently, the application of chimeric antigen receptor (CAR)-T cells in immunotherapy has achieved remarkable therapeutic effects. A similar strategy has been used to generate CAR-iNKT cells, and these CAR-iNKT cells directly kill tumor cells by targeting tumor cell surface antigens. 5, 6 Clinical trials using CAR-iNKT cells specific for the ganglioside GD2 (NCT02439788 and NCT03294954) and CD19-specific CAR-iNKT cells (NCT03774654) have been launched against …