Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.
Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands.
Cancer Immunol Res. 2017 Jul;5(7):535-546. doi: 10.1158/2326-6066.CIR-16-0309. Epub 2017 May 23.
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. .
需要新的免疫治疗策略来诱导所有癌症患者产生有效的抗肿瘤免疫。恶性间皮瘤的预后较差，对常规治疗有抵抗力。肿瘤相关巨噬细胞（TAM）在间皮瘤中浸润明显，并与免疫抑制、血管生成和肿瘤侵袭性有关。因此，TAM 的耗竭可能会重新激活抗肿瘤免疫。我们表明，使用 CSF-1R 激酶抑制剂 PLX3397（pexidartinib）抑制 M-CSFR 可有效减少 TAMs、循环非经典单核细胞以及间皮瘤小鼠模型中的新生血管生成和腹水的数量，但不能提高生存率。当与树突状细胞疫苗接种联合使用时，生存得到协同增强，同时 TAMs 减少，CD8 T 细胞数量和功能增加。与组合疗法治疗的小鼠肿瘤组织中的总 T 细胞和肿瘤抗原特异性 CD8 T 细胞表现出程序性细胞死亡蛋白-1（PD-1）表面表达减少，这与 T 细胞衰竭有关。最后，接受联合治疗的小鼠可免受肿瘤再挑战，并显示出更好的 T 细胞记忆反应。我们报告说，减少局部 TAM 介导的免疫抑制而不激活免疫并不能提高生存率。然而，TAM 介导的免疫抑制与树突状细胞免疫疗法的联合使用可产生强大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 细胞与 TAM 之间的相互作用提供了深入了解，并为间皮瘤治疗提供了一种治疗策略。
