Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth.
Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth.
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DOI：
10.1080/2162402x.2018.1480286
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发表时间：
2018
期刊：
影响因子：
7.2
通讯作者：
Welm AL
中科院分区：
文献类型：
--
作者：
Ekiz HA;Lai SA;Gundlapalli H;Haroun F;Williams MA;Welm AL
免疫检查点阻断作为一种新的免疫治疗策略的出现改变了许多侵袭性癌症的前景。虽然在某些情况下可以实现完全的肿瘤根除，但仅在一小部分患者中观察到持久的临床反应，这突出了迫切需要改进。我们以前的研究表明，罗恩，一种在巨噬细胞中表达的受体酪氨酸激酶，抑制抗肿瘤免疫反应，并促进乳腺癌的进展和转移。在这里，我们研究了巨噬细胞中罗恩激活下游发生的分子变化，以及罗恩的抑制是否可以与检查点免疫疗法合作根除肿瘤。通过其配体MSP激活罗恩，极大地改变了巨噬细胞的基因表达谱，并上调了CD 80和PD-L1（T细胞检查点受体CTLA-4和PD-1的配体）的表面水平。与单药治疗组相比，罗恩的遗传缺失或药理学抑制与抗CTLA-4联合，但不与抗PD-1联合，导致对原位移植肿瘤的临床应答改善，导致46%的动物完全根除肿瘤。对治疗的积极反应与较高水平的T细胞活化标志物和肿瘤浸润淋巴细胞相关。重要的是，罗恩和抗CTLA-4的共同抑制也能有效清除肺部转移性乳腺癌细胞，导致近60%的小鼠出现临床反应。这些发现表明，罗恩抑制可以是增强乳腺癌中对检查点免疫疗法的应答的新方法。
The advent of immune checkpoint blockade as a new strategy for immunotherapy has changed the outlook for many aggressive cancers. Although complete tumor eradication is attainable in some cases, durable clinical responses are observed only in a small fraction of patients, underlining urgent need for improvement. We previously showed that RON, a receptor tyrosine kinase expressed in macrophages, suppresses antitumor immune responses, and facilitates progression and metastasis of breast cancer. Here, we investigated the molecular changes that occur downstream of RON activation in macrophages, and whether inhibition of RON can cooperate with checkpoint immunotherapy to eradicate tumors. Activation of RON by its ligand, MSP, altered the gene expression profile of macrophages drastically and upregulated surface levels of CD80 and PD-L1, ligands for T-cell checkpoint receptors CTLA-4 and PD-1. Genetic deletion or pharmacological inhibition of RON in combination with anti-CTLA-4, but not with anti-PD-1, resulted in improved clinical responses against orthotopically transplanted tumors compared to single-agent treatment groups, resulting in complete tumor eradication in 46% of the animals. Positive responses to therapy were associated with higher levels of T-cell activation markers and tumor-infiltrating lymphocytes. Importantly, co-inhibition of RON and anti-CTLA-4 was also effective in clearing metastatic breast cancer cells in lungs, resulting in clinical responses in nearly 60% of the mice. These findings suggest that RON inhibition can be a novel approach to potentiate responses to checkpoint immunotherapy in breast cancer.