BTK Inhibition Reverses MDSC-Mediated Immunosuppression and Enhances Response to Anti-PDL1 Therapy in Neuroblastoma.
BTK Inhibition Reverses MDSC-Mediated Immunosuppression and Enhances Response to Anti-PDL1 Therapy in Neuroblastoma.
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BTK抑制逆转MDSC介导的免疫抑制，并增强神经母细胞瘤对抗PDL 1治疗的反应。
DOI：
10.3390/cancers13040817
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发表时间：
2021-02-16
期刊：
影响因子：
5.2
通讯作者：
Joshi S
中科院分区：
文献类型：
--
作者：
Ishfaq M;Pham T;Beaman C;Tamayo P;Yu AL;Joshi S
神经母细胞瘤(NB)是最常见的儿童恶性肿瘤，尽管进行了包括免疫治疗在内的先进治疗，但这种高危疾病的患者预后较差。髓系来源的抑制细胞(MDSC)经常聚集在NB肿瘤中，它们诱导免疫抑制并阻碍有效的抗肿瘤免疫反应。在本研究中，我们观察到Bruton氏酪氨酸激酶(BTK)在Nb肿瘤小鼠脾中分离的单核和粒细胞MDSCs中高表达，BTK抑制剂ibrutinib的应用减少了Nb肿瘤小鼠MDSC介导的免疫抑制，肿瘤生长，并增强了抗PDL1检查点抑制治疗。这些研究表明，伊布鲁替尼可以作为一种有前途的治疗药物来控制MDSC介导的NB免疫抑制。MDSCs是髓系免疫细胞，在促进肿瘤生长中起着关键作用。MDSCs在荷瘤宿主中的扩张降低了检查点抑制剂和CAR-T疗法的疗效，因此，耗尽或阻止MDSCs招募的策略在改善包括NB在内的各种癌症的免疫治疗反应方面显示出好处。伊布鲁替尼是一种不可逆转的BTK分子抑制剂，在B细胞恶性肿瘤中得到了广泛的研究，最近该药物被重新用于实体瘤的治疗。在此，我们报道了BTK在从携带NB肿瘤的小鼠分离的粒细胞和单核细胞中都高度表达，并且它的表达增加与NB患者较差的无复发生存概率有关。此外，体外培养的小鼠骨髓间充质干细胞经伊布鲁替尼处理后，NO的产生发生改变，IDO、Arg、转化生长因子β的基因表达降低，T细胞抑制功能出现缺陷。与这些发现一致的是，伊布鲁替尼体内抑制BTK导致MDSC介导的免疫抑制减少，CD8+T细胞浸润增加，肿瘤生长减少，并改善了对抗PDL1检查点抑制剂治疗的反应。这些结果表明，伊布鲁替尼调节MDSC的免疫抑制功能，可以单独使用或与免疫治疗联合使用，以增强NB的抗肿瘤免疫反应。
Neuroblastoma (NB) is the most common pediatric malignancy, and patients with the high-risk disease show a worse prognosis despite advanced treatments, including immunotherapy. Myeloid-derived suppressor cells (MDSC) frequently accumulate in NB tumors, where they induce immunosuppression and hamper efficient antitumor immune responses. In the current study, we observed that Bruton’s tyrosine kinase (BTK) is highly expressed in both monocytic and granulocytic MDSCs isolated from spleens of mice bearing NB tumors and administration of BTK inhibitor ibrutinib reduced MDSC-mediated immunosuppression, tumor growth, and enhanced anti-PDL1 checkpoint inhibitor therapy in mice bearing NB tumors. These studies demonstrated that ibrutinib could serve as a promising therapeutic agent to control MDSC-mediated immune suppression in NB. MDSCs are immune cells of myeloid lineage that plays a key role in promoting tumor growth. The expansion of MDSCs in tumor-bearing hosts reduces the efficacy of checkpoint inhibitors and CAR-T therapies, and hence strategies that deplete or block the recruitment of MDSCs have shown benefit in improving responses to immunotherapy in various cancers, including NB. Ibrutinib, an irreversible molecular inhibitor of BTK, has been widely studied in B cell malignancies, and recently, this drug is repurposed for the treatment of solid tumors. Herein we report that BTK is highly expressed in both granulocytic and monocytic murine MDSCs isolated from mice bearing NB tumors, and its increased expression correlates with a poor relapse-free survival probability of NB patients. Moreover, in vitro treatment of murine MDSCs with ibrutinib altered NO production, decreased mRNA expression of Ido, Arg, Tgfβ, and displayed defects in T-cell suppression. Consistent with these findings, in vivo inhibition of BTK with ibrutinib resulted in reduced MDSC-mediated immune suppression, increased CD8+ T cell infiltration, decreased tumor growth, and improved response to anti-PDL1 checkpoint inhibitor therapy in a murine model of NB. These results demonstrate that ibrutinib modulates immunosuppressive functions of MDSC and can be used either alone or in combination with immunotherapy for augmenting antitumor immune responses in NB.
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