Combination therapy with anti-programmed cell death 1 antibody plus angiokinase inhibitor exerts synergistic antitumor effect against malignant mesothelioma via tumor microenvironment modulation
Combination therapy with anti-programmed cell death 1 antibody plus angiokinase inhibitor exerts synergistic antitumor effect against malignant mesothelioma via tumor microenvironment modulation
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DOI：
10.1016/j.lungcan.2023.107219
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发表时间：
2023-05-03
期刊：
影响因子：
5.3
通讯作者：
Kijima，Takashi
中科院分区：
文献类型：
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作者：
Tada，Akio;Minami，Toshiyuki;Kijima，Takashi
恶性胸膜间皮瘤（MPM）是一种与石棉相关的致命性恶性肿瘤。尽管二十年来除了顺铂和培美曲塞联合治疗外还没有可靠的化疗方案，但伊匹单抗联合纳武单抗为MPM患者带来了更好的预后。因此，使用免疫检查点抑制剂（ICI）的癌症免疫疗法有望在 MPM 的治疗中发挥核心作用。为了最大限度地发挥 ICI 的抗肿瘤作用，我们评估了抗血管生成剂尼达尼布是否可以增强抗程序性细胞死亡 1 (PD-1) 抗体 (Ab) 的抗肿瘤作用。尽管尼达尼布在体外不能抑制间皮瘤细胞的增殖，但它显着抑制小鼠同种异体间皮瘤移植物的生长。此外，与尼达尼布单一疗法相比，抗 PD-1 Ab 加尼达尼布的联合疗法通过诱导 MPM 同种异体移植物显着坏死，更显着地减轻了肿瘤负荷。当单独使用或与抗 PD-1 Ab 联合使用时，尼达尼布不会促进肿瘤内 CD8+T 细胞的浸润，但它独立地减少肿瘤相关巨噬细胞 (TAM) 的浸润。此外，免疫组织化学分析和使用骨髓源性巨噬细胞（BMDM）的离体研究表明，尼达尼布可以将 TAM 从 M2 表型极化为 M1 表型。这些结果表明尼达尼布具有在数量和功能上抑制 TAM 促肿瘤活性的潜力。另一方面，离体研究表明，尼达尼布分别上调BMDM和间皮瘤细胞中PD-1和PD-配体1（PD-L1）的表达，并表现出BMDM对间皮瘤细胞的吞噬活性受损。抗 PD-1 Ab 的共同给药可能会通过 BMDM 上的 PD-1 与间皮瘤细胞上的 PD-L1 之间的结合破坏尼达尼布诱导的免疫抑制信号，从而重新激活 BMDM 的吞噬活性。总的来说，抗PD-1抗体加尼达尼布的联合治疗与各自的单药治疗相比增强了抗肿瘤活性，可以成为MPM患者的一种新的治疗选择。
Malignant pleural mesothelioma (MPM) is an asbestos-related fatal malignant neoplasm. Although there has been no reliable chemotherapeutic regimen other than combination therapy of cisplatin and pemetrexed for two decades, combination of ipilimumab plus nivolumab brought about a better outcome in patients with MPM. Thus, cancer immunotherapy using immune checkpoint inhibitor (ICI) is expected to play a central role in the treatment of MPM. To maximize the antitumor effect of ICI, we evaluated whether nintedanib, an antiangiogenic agent, could augment the antitumor effect of anti-programmed cell death 1 (PD-1) antibody (Ab). Although nintedanib could not inhibit the proliferation of mesothelioma cellsin vitro, it significantly suppressed the growth of mesothelioma allografts in mice. Moreover, combination therapy with anti-PD-1 Ab plus nintedanib reduced tumor burden more dramatically compared with nintedanib monotherapy via inducing remarkable necrosis in MPM allografts. Nintedanib did not promote the infiltration of CD8+T cells within the tumor when used alone or in combination with anti-PD-1 Ab but it independently decreased the infiltration of tumor-associated macrophages (TAMs). Moreover, immunohistochemical analysis andex vivostudy using bone marrow-derived macrophages (BMDMs) showed that nintedanib could polarize TAMs from M2 to M1 phenotype. These results indicated that nintedanib had a potential to suppress protumor activity of TAMs both numerically and functionally. On the other hand,ex vivostudy revealed that nintedanib upregulated the expression of PD-1 and PD-ligand 1 (PD-L1) in BMDMs and mesothelioma cells, respectively, and exhibited the impairment of phagocytic activity of BMDMs against mesothelioma cells. Co-administration of anti-PD-1 Ab may reactivate phagocytic activity of BMDMs by disrupting nintedanib-induced immunosuppressive signal via binding between PD-1 on BMDMs and PD-L1 on mesothelioma cells. Collectively, combination therapy of anti-PD-1 Ab plus nintedanib enhances the antitumor activity compared with respective monotherapy and can become a novel therapeutic option for patients with MPM.