Dana C. Baiu, Akshat Sharma, Jennifer L. Schehr, Jayati Basu, Kelsey A. Smith, Makoto Ohashi, Eric C. Johannsen, Shannon C. Kenney, Jenny E. Gumperz
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Using live cell imaging, we found that CD4<sup>−</sup> iNKT cells limited growth of CD1d<sup>+</sup> Epstein–Barr virus (EBV)-infected B-lymphoblastoid spheroids in vitro, whereas CD4<sup>+</sup> iNKT cells showed little or no direct anti-tumour activity. However, the effects of the two subsets were reversed when we tested them as adoptive immunotherapies in vivo using a xenograft model of EBV-driven human B cell lymphoma. We found that EBV-infected B cells down-regulated CD1d in vivo, and administering CD4<sup>−</sup> iNKT cells had no discernable impact on tumour mass. In contrast, xenotransplanted mice bearing lymphomas showed rapid reduction in tumour mass after administering CD4<sup>+</sup> iNKT cells. Immunotherapeutic CD4<sup>+</sup> iNKT cells trafficked to both spleen and tumour and were associated with subsequently enhanced responses of xenotransplanted human T cells against EBV. 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引用次数: 0
摘要
不变自然杀伤 T(iNKT)细胞是一种保守的先天性 T 淋巴细胞,由于缺乏异体活性,因此非常适合作为现成的细胞免疫疗法。人类 iNKT 细胞有两个主要亚群,一个是具有 TH1/溶解特征的 CD4- 亚群,另一个是 CD4+ 亚群,后者似乎具有多种功能,可产生调节性和免疫刺激性细胞因子。这两个亚群在抗肿瘤作用方面是否存在差异尚不清楚。通过活细胞成像,我们发现 CD4- iNKT 细胞在体外限制了 CD1d+ Epstein-Barr 病毒(EBV)感染的 B 淋巴细胞球体的生长,而 CD4+ iNKT 细胞几乎没有直接的抗肿瘤活性。然而,当我们使用 EBV 驱动的人类 B 细胞淋巴瘤异种移植模型对这两个亚群进行体内采用性免疫疗法测试时,它们的效果却发生了逆转。我们发现,EBV 感染的 B 细胞在体内会下调 CD1d,而施用 CD4- iNKT 细胞对肿瘤质量没有明显影响。相反,异种移植淋巴瘤小鼠在注射 CD4+ iNKT 细胞后,肿瘤体积迅速缩小。具有免疫治疗作用的 CD4+ iNKT 细胞可迁移到脾脏和肿瘤,并与随后增强的异种移植人类 T 细胞对 EBV 的反应有关。CD4+ iNKT细胞对单核细胞衍生的DC也有类似佐剂的作用,并促进体外人类T细胞的抗原依赖性反应。这些结果表明,同种异体 CD4+ iNKT 细胞免疫疗法通过间接途径产生明显的抗肿瘤活性,这种途径不需要肿瘤细胞 CD1d 的表达,而且与抗原特异性 T 细胞活性的增强有关。
Human CD4+ iNKT cell adoptive immunotherapy induces anti-tumour responses against CD1d-negative EBV-driven B lymphoma
Invariant natural killer T (iNKT) cells are a conserved population of innate T lymphocytes that are uniquely suitable as off-the-shelf cellular immunotherapies due to their lack of alloreactivity. Two major subpopulations of human iNKT cells have been delineated, a CD4− subset that has a TH1/cytolytic profile, and a CD4+ subset that appears polyfunctional and can produce both regulatory and immunostimulatory cytokines. Whether these two subsets differ in anti-tumour effects is not known. Using live cell imaging, we found that CD4− iNKT cells limited growth of CD1d+ Epstein–Barr virus (EBV)-infected B-lymphoblastoid spheroids in vitro, whereas CD4+ iNKT cells showed little or no direct anti-tumour activity. However, the effects of the two subsets were reversed when we tested them as adoptive immunotherapies in vivo using a xenograft model of EBV-driven human B cell lymphoma. We found that EBV-infected B cells down-regulated CD1d in vivo, and administering CD4− iNKT cells had no discernable impact on tumour mass. In contrast, xenotransplanted mice bearing lymphomas showed rapid reduction in tumour mass after administering CD4+ iNKT cells. Immunotherapeutic CD4+ iNKT cells trafficked to both spleen and tumour and were associated with subsequently enhanced responses of xenotransplanted human T cells against EBV. CD4+ iNKT cells also had adjuvant-like effects on monocyte-derived DCs and promoted antigen-dependent responses of human T cells in vitro. These results show that allogeneic CD4+ iNKT cellular immunotherapy leads to marked anti-tumour activity through indirect pathways that do not require tumour cell CD1d expression and that are associated with enhanced activity of antigen-specific T cells.
期刊介绍:
Immunology is one of the longest-established immunology journals and is recognised as one of the leading journals in its field. We have global representation in authors, editors and reviewers.
Immunology publishes papers describing original findings in all areas of cellular and molecular immunology. High-quality original articles describing mechanistic insights into fundamental aspects of the immune system are welcome. Topics of interest to the journal include: immune cell development, cancer immunology, systems immunology/omics and informatics, inflammation, immunometabolism, immunology of infection, microbiota and immunity, mucosal immunology, and neuroimmunology.
The journal also publishes commissioned review articles on subjects of topical interest to immunologists, and commissions in-depth review series: themed sets of review articles which take a 360° view of select topics at the heart of immunological research.