CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：NEDD8-activating enzyme inhibition potentiates the anti-myeloma activity of natural killer cells.
NEDD8-activating enzyme inhibition potentiates the anti-myeloma activity of natural killer cells.
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自然杀伤（NK）细胞在血液系统恶性肿瘤的发生和进展中充当重要的调节因子，其针对多发性骨髓瘤（MM）细胞的抑制活性已在许多研究中得到证实。在MM患者中描述了NK细胞亚群分布的显著变化以及NK细胞效应功能的异常，并与疾病分期相关。
因此，恢复或增强这些效应细胞的功能以治疗MM代表了一项关键需求。Neddylation是一种翻译后修饰，将类泛素分子NEDD8添加到靶蛋白上。其结果之一是激活Cullin Ring Ligases（CRLs），这是一类泛素连接酶，控制约20%蛋白酶体调节蛋白的降解。CRLs的过度激活已在癌症中被描述，并可导致肿瘤生长和进展。
因此，靶向neddylation代表了一种有吸引力的癌症治疗方法。我们课题组最近描述了neddylation的药理学抑制如何增加MM细胞中NKG2D激活受体配体MICA和MICB的表达，使这些细胞更容易受到NK细胞脱颗粒和杀伤。
在此，我们将研究扩展到neddylation对NK细胞针对MM发挥的效应功能的直接作用。我们观察到，neddylation的抑制增强了NK细胞介导的针对MM细胞的脱颗粒和杀伤，并改善了Daratumumab/Elotuzumab介导的反应。在机制上，抑制neddylation增加了NK细胞中Rac1和RhoA GTPases的表达，这些是细胞毒性淋巴细胞免疫突触处有效脱颗粒的关键介质，并增加了与靶细胞接触的NK细胞中F-actin和穿孔素的极化水平。
此外，抑制neddylation部分消除了TGF介导的NK细胞效应活性的抑制。本研究描述了neddylation在NK细胞效应功能中的作用，并强调了在MM中通过抑制该通路所实现的积极免疫调节效应。
Natural Killer (NK) cells act as important regulators in the development and progression of hematological malignancies and their suppressor activity against Multiple Myeloma (MM) cells has been confirmed in many studies. Significant changes in the distribution of NK cell subsets and dysfunctions of NK cell effector activities were described in MM patients and correlated with disease staging.
Thus, restoring or enhancing the functionality of these effectors for the treatment of MM represents a critical need. Neddylation is a post-translational modification that adds a ubiquitin-like molecule, NEDD8, to the substrate protein. One of the outcomes is the activation of the Cullin Ring Ligases (CRLs), a class of ubiquitin-ligases that controls the degradation of about 20% of proteasome-regulated proteins. Overactivation of CRLs has been described in cancer and can lead to tumor growth and progression.
Thus, targeting neddylation represents an attractive approach for cancer treatment.
Our group has recently described how pharmacologic inhibition of neddylation increases the expression of the NKG2D activating receptor ligands, MICA and MICB, in MM cells, making these cells more susceptible to NK cell degranulation and killing.
Here, we extended our investigation to the direct role of neddylation on NK cell effector functions exerted against MM.
We observed that inhibition of neddylation enhanced NK cell-mediated degranulation and killing against MM cells and improved Daratumumab/Elotuzumab-mediated response.
Mechanistically, inhibition of neddylation increased the expression of Rac1 and RhoA GTPases in NK cells, critical mediators for an efficient degranulation at the immunological synapse of cytotoxic lymphocytes, and augmented the levels of F-actin and perforin polarization in NK cells contacting target cells.
Moreover, inhibition of neddylation partially abrogated TGF -mediated repression of NK cell effector activity. This study describes the role of neddylation on NK cell effector functions and highlights the positive immunomodulatory effects achieved by the inhibition of this pathway in MM.
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