Zingoni Alessandra, Vulpis Elisabetta, Nardone Ilaria, Soriani Alessandra, Fionda Cinzia, Cippitelli Marco, Santoni Angela
Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy.
Laboratory of Immunology and Immunopathology, Department of Molecular Medicine and Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Universita di Roma, Rome, Italy.
Crit Rev Immunol. 2016;36(6):445-460. doi: 10.1615/CritRevImmunol.2017020166.
Natural killer (NK) cells are critical immune effector cells capable of mediating antitumor responses. These cytotoxic lymphocytes recognize transformed cells through a mechanism mainly dependent on the engagement of several activating receptors. However, many tumors have developed strategies to evade immunosurveillance and detection by NK cells. A relevant immune escape mechanism is the down regulation of NK cell activating ligands on the surface of tumor cells by proteolytic shedding mediated by different members of metalloproteinase families. Here, we consider two important NK activating receptors, namely NKG2D and NKp30, the ligands (i.e., MICA/B, ULBPs, and B7-H6) of which can be released by cancer cells through proteolytic cleavage. Modulation of ligand shedding in response to cancer therapy is also examined, and we discuss how metalloproteinases implicated in the ligand cleavage could be targeted in novel therapeutic schemes to counteract tumor escape from stress-elicited immune responses.
自然杀伤（NK）细胞是能够介导抗肿瘤反应的关键免疫效应细胞。这些细胞毒性淋巴细胞通过一种主要依赖于几种激活受体相互作用的机制识别转化细胞。然而，许多肿瘤已经发展出逃避NK细胞免疫监视和检测的策略。一种相关的免疫逃逸机制是通过金属蛋白酶家族不同成员介导的蛋白水解脱落，下调肿瘤细胞表面NK细胞激活配体。在这里，我们考虑两种重要的NK激活受体，即NKG2D和NKp30，其配体（即MICA/B、ULBPs和B7-H6）可被癌细胞通过蛋白水解切割释放。还研究了癌症治疗对配体脱落的调节作用，并且我们讨论了如何在新的治疗方案中靶向参与配体切割的金属蛋白酶，以对抗肿瘤从应激引发的免疫反应中逃逸。
