Department of Hematology, Oncology, and Tumor Immunology (CVK), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Department of Hematology, Oncology, and Tumor Immunology (CCM), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Oncoimmunology. 2022 Apr 25;11(1):2068109. doi: 10.1080/2162402X.2022.2068109. eCollection 2022.
Immunostimulatory regimens are a game changer in the fight against cancer, but still only a minority of patients achieve clinical benefit. Combination with immunomodulatory drugs and agents converting otherwise non-immunogenic forms of cell death into bona fide "immunogenic cell death" (ICD) could improve the efficacy of these novel therapies. The aim of our study was to investigate conventional Amphotericin B (AmB) as an enhancer of antitumor immune responses. In tumor cell line models, AmB induced ICD with its typical hallmarks of calreticulin (CALR) expression and release of high mobility group box 1 (HMGB1) as well as Adenosine 5'-triphosphate (ATP). Interestingly, in contrast to non-ICD inducing treatments, ICD induction led to up-regulation of PD-L1-expression by ICD experiencing cells, resulting in decreased maturation of dendritic cells (DCs). Blocking this PD-L1 expression on tumor cells could unleash full ICD effects on antigen presenting cells. Even at sub-toxic concentrations, AmB was able to enhance CALR on leukemic blasts, particularly on phagocytic monoblastic THP-1 cells, which also showed features of "M1-like" differentiation after AmB exposure. The ability of AmB to increase the immunogenicity of tumor cells was confirmed in vivo in a mouse vaccination experiment. In conclusion, we demonstrate that AmB can promote antitumor immune responses in a dose-dependent manner by ICD induction, surface translocation of CALR on leukemic blasts even at sub-toxic concentrations, and "M1-like" polarization of phagocytic cells, making it noteworthy as potential booster for cancer immunotherapy. We additionally report for the first time that PD-L1 expression may be a feature of ICD, possibly as a negative feedback mechanism regulating the maturation status of DCs and thus indirectly affecting T-cell priming.
免疫刺激方案是抗击癌症的游戏规则改变者，但仍只有少数患者获得临床获益。与免疫调节药物和将原本非免疫原性的细胞死亡形式转化为真正的“免疫原性细胞死亡”（ICD）的药物联合使用，可以提高这些新型疗法的疗效。我们的研究目的是研究常规两性霉素 B（AmB）作为增强抗肿瘤免疫反应的增强剂。在肿瘤细胞系模型中，AmB 诱导 ICD，其典型特征是钙网蛋白（CALR）表达和高迁移率族蛋白 1（HMGB1）以及三磷酸腺苷（ATP）的释放。有趣的是，与非 ICD 诱导治疗相反，ICD 诱导导致 ICD 经历细胞上调 PD-L1 表达，导致树突状细胞（DC）成熟减少。阻断肿瘤细胞上的这种 PD-L1 表达可以释放出抗原呈递细胞上的全部 ICD 效应。即使在亚毒性浓度下，AmB 也能够增强白血病细胞上的 CALR，特别是在吞噬单核源性 THP-1 细胞上，在 AmB 暴露后也显示出“M1 样”分化的特征。AmB 在体内小鼠疫苗实验中证实了其增加肿瘤细胞免疫原性的能力。总之，我们证明 AmB 可以通过 ICD 诱导、甚至在亚毒性浓度下白血病细胞表面 CALR 的易位以及吞噬细胞的“M1 样”极化以剂量依赖性方式促进抗肿瘤免疫反应，使其成为癌症免疫治疗的潜在增强剂。我们还首次报道 PD-L1 表达可能是 ICD 的一个特征，可能作为调节 DC 成熟状态的负反馈机制，从而间接影响 T 细胞的启动。
