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Intratumoral immunotherapy with anti-PD-1 and TLR9 agonist induces systemic antitumor immunity without accelerating rejection of cardiac allografts.

Anti-PD-1 和 TLR9 激动剂的瘤内免疫治疗诱导全身抗肿瘤免疫,而不加速心脏同种异体移植物的排斥反应。

  • 影响因子:4.55
  • DOI:10.1111/ajt.16105
  • 作者列表:"Dang N","Waer M","Sprangers B","Lin Y
  • 发表时间:2020-06-07
Abstract

:Immune checkpoint inhibitors, such as PD-1 blockades, have revolutionized the field of cancer immunotherapy. However, there is a growing concern whether PD-1 inhibitors can be safely administered to transplant recipients with advanced cancer as the T cells activated by checkpoint inhibitors may become reactive not only towards tumor antigens but also towards donor alloantigen resulting in allograft rejection. Here, immunotherapy with anti-PD-1/TLR9 agonist was administered to C57BL/6 mice bearing a cardiac allograft receiving maintenance immunosuppression or a PI4KIIIβ inhibitors-based tolerogenic regimen. Intratumoral (i.t.), but not systemic, immunotherapy promoted potent anti-tumor responses, but did not accelerated allograft rejection. This effect was associated with a pro-immunogenic effect induced by i.t. immunotherapy resulting in systemic cellular and humoral immune anti-tumor responses. Furthermore, when the tumor and cardiac allograft shared MHC antigens, i.t. immunotherapy promoted immune responses directed against tumor and the cardiac allograft resulting in allograft rejection. The anti-tumor effect was compromised by maintenance immunosuppression with cyclosporine A, indicating that an optimal balance between enhanced anti-tumor immunity and decreased transplant immunoreactivity is critical. A clinically relevant approach could be to temporary withdrawal maintenance immunosuppression and/or replace it by a PI4KIIIβ inhibitors-based tolerance inducing regimen to allow for effective immunotherapy to take place.

摘要

: 免疫检查点抑制剂,如 PD-1 封锁,彻底改变了癌症免疫治疗领域。然而,由于检查点抑制剂激活的 T 细胞不仅对肿瘤抗原具有反应性,而且对供体同种抗原也具有反应性,因此人们越来越担心 PD-1 抑制剂是否可以安全地用于晚期癌症的移植受者。在同种异体移植排斥反应中。这里,将 anti-PD-1/TLR9 激动剂免疫治疗给予 C57BL/6 小鼠移植心脏,接受维持免疫抑制或基于 pi4kiii β 抑制剂的耐受性方案。瘤内 (i.t.),但不是全身的,免疫治疗促进了强效的抗肿瘤反应,但没有加速同种异体排斥反应。该效应与 i.t.诱导的促免疫原性效应相关。免疫治疗导致全身细胞和体液免疫抗肿瘤反应。此外,当肿瘤和心脏移植物共享 MHC 抗原时,i.t.免疫治疗促进了针对肿瘤和心脏同种异体移植物的免疫反应,导致同种异体移植物排斥。环孢素a 维持免疫抑制降低了抗肿瘤作用,表明增强抗肿瘤免疫和降低移植免疫反应性之间的最佳平衡至关重要。临床相关的方法可以是暂时停药维持免疫抑制和/或用基于 pi4kiii β 抑制剂的耐受诱导方案替代,以允许进行有效的免疫治疗。

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