CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：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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肝素与 ACT 或 anti-PD1 联合治疗产生了协同抗肿瘤效应，其机制至少部分通过肿瘤血管正常化实现，从而因 Treg 浸润减少和 M1 巨噬细胞极化增加而增强了抗肿瘤 T 细胞应答。这种协同联合治疗值得临床评估。参见 Korc 的相关评论，第 2348 页。
胰腺导管腺癌（PDA）对过继细胞转移（ACT）和免疫检查点抑制剂治疗具有耐药性。理解这种耐药性的机制将改善PDA的免疫治疗。本研究探讨了抗凝药物对PDA免疫治疗的治疗效果及其潜在机制。
在 desert、excluded 和 inflamed 肿瘤小鼠模型中评估了免疫疗法的抗肿瘤活性。通过免疫荧光成像分析免疫细胞浸润，并通过间质液压力和凝血状态测量分析肿瘤微循环，从而探究其潜在机制。
肝素与ACT联合使用可抑制肿瘤生长和转移，而单用肝素或ACT均无任何治疗效果。肝素与ACT联合可显著增加CD8+ T细胞和M1巨噬细胞的瘤内浸润，并减少免疫抑制性M2巨噬细胞和FOXP3+/CD4+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残余血管正常化，从而促进活化CD8+ T细胞向肿瘤的血管外渗及血管周围积聚。在机制上，肝素显著改善了肿瘤微血管血流动力学特性，这与其对肿瘤血管生成的抑制作用一致。同样，肝素与抗PD1联合也产生了显著的抗肿瘤活性，而单用肝素或抗PD1治疗均无明显抗肿瘤活性。
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 immunotherapy 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.
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+ T cells and M1 macrophages and reduced the infiltration of immunosuppressive M2 macrophages and FOXP3+/CD4+ 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 accumulation of activated CD8+ 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.
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 antitumor T-cell responses due to reduced Treg infiltration and increased M1 macrophage polarization. This synergistic combination therapy warrants clinical evaluation. See related commentary by Korc, p. 2348.
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