Anti-PD-1/PD-L1 therapy augments lenvatinib's efficacy by favorably altering the immune microenvironment of murine anaplastic thyroid cancer
Anti-PD-1/PD-L1 therapy augments lenvatinib's efficacy by favorably altering the immune microenvironment of murine anaplastic thyroid cancer
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DOI：
10.1002/ijc.32041
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发表时间：
2019-05-01
影响因子：
6.4
通讯作者：
Parangi, Sareh
中科院分区：
文献类型：
--
作者：
Gunda, Viswanath;Gigliotti, Benjamin;Parangi, Sareh
甲状腺未分化癌（ATC）患者的预后极差，尽管采用手术和放化疗的多模式治疗。Lenvatinib是一种多靶点酪氨酸激酶抑制剂，以及靶向程序性细胞死亡途径的检查点抑制剂，已被证明对某些晚期甲状腺癌患者有效。这些疗法的组合是一种潜在的手段，以提高有效性和最大限度地减少治疗耐药性的ATC。我们利用我们的新型原位ATC免疫活性小鼠模型证明乐伐替尼可显著缩小肿瘤并提高生存率，而联合治疗可显著改善两者。乐伐替尼单药治疗增加了肿瘤浸润性巨噬细胞、CD 8（+）T细胞、调节性T细胞，最值得注意的是，多形核细胞髓源性抑制细胞（PMN-MDSC）。虽然两种联合治疗均导致CD 8（+）T细胞进一步增加，但仅乐伐替尼和抗PD-1联合治疗可降低PMN-MDSC。在接受乐伐替尼治疗ATC的小鼠和1例患者的血液中也观察到PMN-MDSC扩增。在我们的小鼠模型中使用的ATC细胞系的RNA-Seq证明，乐伐替尼对血管生成、对缺氧的反应、上皮细胞向间充质细胞的转化以及与炎症和宿主免疫有关的多种途径具有多方面的影响。乐伐替尼与抗Gr-1抗体联合使用改善了乐伐替尼对MDSC的扩增，并显著提高了乐伐替尼的抗肿瘤作用。这些数据表明，MDSC在ATC对乐伐替尼的反应中起负面作用，并支持未来研究其作为潜在生物标志物和治疗靶点的作用。
Patients with anaplastic thyroid cancer (ATC) have an extremely poor prognosis despite multimodal therapy with surgery and chemoradiation. Lenvatinib, a multi-targeted tyrosine kinase inhibitor, as well as checkpoint inhibitors targeting the programmed cell death pathway, have proven effective in some patients with advanced thyroid cancer. Combination of these therapies is a potential means to boost effectiveness and minimize treatment resistance in ATC. We utilized our novel immunocompetent murine model of orthotopic ATC to demonstrate that lenvatinib led to significant tumor shrinkage and increased survival, while combination therapy led to dramatic improvements in both. Lenvatinib monotherapy increased tumor-infiltrating macrophages, CD8(+) T-cells, regulatory T-cells, and most notably, polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs). While both combination therapies led to further increases in CD8(+) T-cells, only the lenvatinib and anti-PD-1 combination decreased PMN-MDSCs. PMN-MDSC expansion was also seen in the blood of mice and one patient receiving lenvatinib therapy for ATC. RNA-Seq of the ATC cell line used in our mouse model demonstrated that lenvatinib has multifaceted effects on angiogenesis, response to hypoxia, the epithelial-to-mesenchymal transition, and on multiple pathways implicated in inflammation and host immunity. Combination of lenvatinib with anti-Gr-1 antibody ameliorated lenvatinib's expansion of MDSCs and significantly improved lenvatinib's anti-tumor effect. These data suggest that MDSCs play a negative role in ATC's response to lenvatinib and support future study of their role as a potential biomarker and treatment target.