Anticoagulants Enhance Molecular and Cellular Immunotherapy of Cancer by Improving Tumor Microcirculation Structure and Function and Redistributing Tumor Infiltrates
Anticoagulants Enhance Molecular and Cellular Immunotherapy of Cancer by Improving Tumor Microcirculation Structure and Function and Redistributing Tumor Infiltrates
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DOI：
10.1158/1078-0432.ccr-22-2757
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发表时间：
2023-07-01
影响因子：
11.5
通讯作者：
Xie, Keping
中科院分区：
文献类型：
--
作者：
Wei, Fang;Su, Yuling;Xie, Keping
目的：胰腺导管腺癌（PDA）抵抗过继细胞转移（ACT）和免疫检查点抑制剂的免疫治疗。了解这种耐药性的机制将改善PDA免疫治疗。本研究探讨了抗凝血剂对PDA.Experimental Design免疫治疗的治疗效果和潜在机制：免疫疗法的抗肿瘤活性进行了评估，在沙漠，排除，和发炎的肿瘤小鼠模型。通过免疫荧光成像分析免疫细胞浸润和肿瘤微循环间质液压力和凝血状态measurement.Results：肝素和ACT联合使用抑制肿瘤生长和转移，而肝素和ACT没有任何治疗效果的潜在机制进行了研究。肝素和ACT的组合显著增加了CD 8刺T细胞和M1巨噬细胞的肿瘤内浸润，并减少了免疫抑制性M2巨噬细胞和FOXP 3刺/CD 4刺调节性T细胞（Treg）的浸润。对肿瘤微环境的评估显示，肝素促进肿瘤血管消退并使剩余血管正常化，促进肿瘤中活化的CD 8刺T细胞的外渗和血管周围聚集。从机制上讲，肝素显著改善了肿瘤微血管的血流动力学特性，这与其抑制肿瘤血管生成的作用一致。类似地，肝素和抗PD 1的组合也产生了显著的抗肿瘤活性，而肝素和抗PD 1治疗都没有明显的抗肿瘤活性。结论：肝素和ACT或抗PD 1的联合治疗产生协同抗肿瘤作用，这至少部分是通过肿瘤血管正常化，因此由于Treg浸润减少和M1巨噬细胞极化增加而增加抗肿瘤T细胞应答。这种协同联合疗法值得临床评价，见Korc的相关评论，第2348页
Purpose: Pancreatic ductal adenocarcinoma (PDA) resists immunotherapy of adoptive cell transfer (ACT) and immune checkpoint inhibitors. Understanding the mechanisms underlying this resistance will improve PDA immunotherapy. This study investigated therapeutic effects and underlying mechanisms of anticoagulants on immunotherapy in PDA.Experimental Design: The antitumor activity of immunother-apy was evaluated in mouse models of desert, excluded, and inflamed tumors. The underlying mechanisms were investigated by analyzing immune cell infiltration by immunofluorescence imaging and tumor microcirculation by interstitial fluid pressure and coagulation status measurement.Results: Combined use of heparin and ACT inhibited tumor growth and metastasis, whereas neither heparin nor ACT had any therapeutic effect. The combination of heparin and ACT significantly increased the intratumor infiltration of CD8 thorn T cells and M1 macrophages and reduced the infiltration of immunosuppressive M2 macrophages and FOXP3 thorn /CD4 thorn regulatory T cells (Treg). Assessments of tumor microenvironment revealed that heparin promoted tumor vascular regression and normalized the remaining blood vessels, facilitating the extravasation and perivascular accu-mulation of activated CD8 thorn T cells in tumors. Mechanistically, tumor microvessel hemodynamic properties were significantly improved by heparin, which is consistent with its inhibitory effects on tumor angiogenesis. Similarly, the combination of heparin and anti-PD1 also produced a pronounced antitumor activity, whereas neither heparin nor anti-PD1 treatment had appreciable antitumor activity. Conclusions: Combined treatment of heparin and ACT or anti-PD1 produced synergistic antitumor effects, which were at least in part through tumor vascular normalization, hence increased anti-tumor T-cell responses due to reduced Treg infiltration and increased M1 macrophage polarization. This synergistic combina-tion therapy warrants clinical evaluation.See related commentary by Korc, p. 2348