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Arming cytotoxic lymphocytes for cancer immunotherapy by means of the NKG2D/NKG2D-ligand system.
Expert Opinion on Biological Therapy ( IF 4.6 ) Pub Date : 2020-08-31 , DOI: 10.1080/14712598.2020.1803273
Mariya Lazarova 1 , Winfried S Wels 2, 3, 4 , Alexander Steinle 1, 3
Affiliation  

ABSTRACT

Introduction

The activating NKG2D receptor plays a central role in the immune recognition and elimination of abnormal self-cells by cytotoxic lymphocytes. NKG2D binding to cell stress-inducible ligands (NKG2DL) up-regulated on cancer cells facilitates their immunorecognition. Yet tumor cells utilize various escape mechanisms to avert NKG2D-based immunosurveillance. Hence, therapeutic strategies targeting the potent NKG2D/NKG2DL axis and such immune escape mechanisms become increasingly attractive in cancer therapy.

Areas covered

This perspective provides a brief introduction into the NKG2D/NKG2DL axis and its relevance for cancer immune surveillance. Subsequently, the most advanced therapeutic approaches targeting the NKG2D system are presented focusing on NKG2D-CAR engineered immune cells and antibody-mediated strategies to inhibit NKG2DL shedding by tumors.

Expert opinion

Thus far, NKG2D-CAR engineered lymphocytes represent the most advanced therapeutic approach utilizing the NKG2D system. Similarly to other tumor-targeting CAR approaches, NKG2D-CAR cells demonstrate powerful on-target activity, but may also cause off-tumor toxicities or lose efficacy, if NKG2DL expression by tumors is reduced. However, NKG2D-CAR cells also act on the tumor microenvironment curtailing its immunosuppressive properties, thus providing an independent therapeutic benefit. The potency of tumoricidal NKG2D-expressing lymphocytes can be further boosted by enhancing NKG2DL expression through small molecules and therapeutic antibodies inhibiting tumor-associated shedding of NKG2DL.



中文翻译:

通过NKG2D / NKG2D-配体系统武装用于癌症免疫治疗的细胞毒性淋巴细胞。

摘要

介绍

活化的NKG2D受体在免疫识别和消除细胞毒性淋巴细胞对异常自身细胞的过程中起着核心作用。NKG2D与在癌细胞上调的细胞应激诱导配体(NKG2DL)的结合有助于其免疫识别。然而,肿瘤细胞利用各种逃逸机制来避免基于NKG2D的免疫监视。因此,靶向有效的NKG2D / NKG2DL轴和这种免疫逃逸机制的治疗策略在癌症治疗中变得越来越有吸引力。

覆盖区域

该观点简要介绍了NKG2D / NKG2DL轴及其与癌症免疫监视的关系。随后,提出了针对NKG2D系统的最先进的治疗方法,重点放在NKG2D-CAR工程改造的免疫细胞和抗体介导的抑制肿瘤释放NKG2DL的策略上。

专家意见

迄今为止,NKG2D-CAR工程淋巴细胞代表了利用NKG2D系统的最先进的治疗方法。与其他靶向肿瘤的CAR方法类似,NKG2D-CAR细胞显示出强大的靶向活性,但是如果肿瘤中NKG2DL的表达减少,NKG2D-CAR细胞也可能引起肿瘤外毒性或丧失疗效。但是,NKG2D-CAR细胞也可通过抑制其免疫抑制特性而作用于肿瘤微环境,从而提供独立的治疗益处。可以通过小分子增强NKG2DL的表达并抑制肿瘤相关性NKG2DL脱落的治疗性抗体进一步增强表达NKG2D的杀伤性淋巴细胞的效力。

更新日期:2020-08-31
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