Depletion of Tumor-Associated Macrophages with a CSF-1R Kinase Inhibitor Enhances Antitumor Immunity and Survival Induced by DC Immunotherapy
Depletion of Tumor-Associated Macrophages with a CSF-1R Kinase Inhibitor Enhances Antitumor Immunity and Survival Induced by DC Immunotherapy
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DOI：
10.1158/2326-6066.cir-16-0309
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发表时间：
2017-07-01
影响因子：
10.1
通讯作者：
Aerts, Joachim G.
中科院分区：
文献类型：
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作者：
Dammeijer, Floris;Lievense, Lysanne A.;Aerts, Joachim G.
需要新的免疫策略来在所有癌症患者中诱导有效的抗肿瘤免疫。恶性间皮瘤的特点是预后差，对常规治疗有抵抗力。肿瘤相关巨噬细胞（TAM）的浸润在间皮瘤中很突出，并与免疫抑制、血管生成和肿瘤侵袭性有关。因此，TAM消耗可能重新激活抗肿瘤免疫。我们发现，使用CSF-1 R激酶抑制剂PLX 3397（pexidartinib）抑制M-CSFR可有效减少间皮瘤小鼠模型中TAM、循环非经典单核细胞的数量以及新血管生成和腹水的数量，但未改善生存期。当与树突状细胞疫苗接种相结合时，存活率协同增强，同时TAM减少，CD 8（+）T细胞数量和功能增加。联合治疗小鼠肿瘤组织中的总的以及肿瘤抗原特异性CD 8（+）T细胞显示程序性细胞死亡蛋白-1（PD-1）的表面表达减少，这是一种与T细胞耗竭相关的现象。最后，用联合疗法治疗的小鼠被保护免于肿瘤再攻击，并显示出优越的上级T细胞记忆应答。我们报告说，减少局部TAM介导的免疫抑制，而没有免疫激活并不能提高生存率。然而，TAM介导的免疫抑制与树突状细胞免疫疗法的组合产生稳健且持久的抗肿瘤免疫。这些发现为免疫治疗诱导的抗肿瘤T细胞和TAM之间的相互作用提供了见解，并为间皮瘤治疗提供了治疗策略。（C）2017年AACR。
New immunotherapeutic strategies are needed to induce effective antitumor immunity in all cancer patients. Malignant mesothelioma is characterized by a poor prognosis and resistance to conventional therapies. Infiltration of tumor-associated macrophages (TAM) is prominent in mesothelioma and is linked to immune suppression, angiogenesis, and tumor aggressiveness. Therefore, TAM depletion could potentially reactivate antitumor immunity. We show that M-CSFR inhibition using the CSF-1R kinase inhibitor PLX3397 (pexidartinib) effectively reduced numbers of TAMs, circulating nonclassical monocytes, as well as amount of neoangiogenesis and ascites in mesothelioma mouse models, but did not improve survival. When combined with dendritic cell vaccination, survival was synergistically enhanced with a concomitant decrease in TAMs and an increase in CD8(+) T-cell numbers and functionality. Total as well as tumor antigen-specific CD8(+) T cells in tumor tissue of mice treated with combination therapy showed reduced surface expression of the programmed cell death protein-1 (PD-1), a phenomenon associated with T-cell exhaustion. Finally, mice treated with combination therapy were protected from tumor rechallenge and displayed superior T-cell memory responses. We report that decreasing local TAM-mediated immune suppression without immune activation does not improve survival. However, combination of TAM-mediated immune suppression with dendritic cell immunotherapy generates robust and durable antitumor immunity. These findings provide insights into the interaction between immunotherapy-induced antitumor T cells and TAMs and offer a therapeutic strategy for mesothelioma treatment. (C)2017 AACR.