PDF(Pubmed)
Abstract：
CD73 is a cell surface 5\'nucleotidase (NT5E) and key node in the catabolic process generating immunosuppressive adenosine in cancer. Using a murine monoclonal antibody surrogate of Oleclumab, we investigated the effect of CD73 inhibition in concert with cytotoxic therapies (chemotherapies as well as fractionated radiotherapy) and PD-L1 blockade. Our results highlight improved survival in syngeneic tumor models of colorectal cancer (CT26 and MC38) and sarcoma (MCA205). This therapeutic outcome was in part driven by cytotoxic CD8 T-cells, as evidenced by the detrimental effect of CD8 depleting antibody treatment of MCA205 tumor bearing mice treated with anti-CD73, anti-PD-L1 and 5-Fluorouracil+Oxaliplatin (5FU+OHP). We hypothesize that the improved responses are tumor microenvironment (TME)-driven, as suggested by the lack of anti-CD73 enhanced cytopathic effects mediated by 5FU+OHP on cell lines in vitro. Pharmacodynamic analysis, using imaging mass cytometry and RNA-sequencing, revealed noteworthy changes in specific cell populations like cytotoxic T cells, B cells and NK cells in the CT26 TME. Transcriptomic analysis highlighted treatment-related modulation of gene profiles associated with an immune response, NK and T-cell activation, T cell receptor signaling and interferon (types 1 & 2) pathways. Inclusion of comparator groups representing the various components of the combination allowed deconvolution of contribution of the individual therapeutic elements; highlighting specific effects mediated by the anti-CD73 antibody with respect to immune-cell representation, chemotaxis and myeloid biology. These pre-clinical data reflect complementarity of adenosine blockade with cytotoxic therapy, and T-cell checkpoint inhibition, and provides new mechanistic insights in support of combination therapy.
摘要：
CD73是细胞表面的核苷酸酶(NT5E),是在癌症中产生免疫抑制性腺苷的分解代谢过程中的关键节点。使用Oleclumab的鼠单克隆抗体替代品，我们研究了CD73抑制与细胞毒性治疗(化疗和分次放疗)和PD-L1阻断的协同作用.我们的结果强调了结直肠癌（CT26和MC38）和肉瘤（MCA205）的同基因肿瘤模型的生存率的提高。这种治疗结果部分是由细胞毒性CD8T细胞驱动的，CD8耗竭抗体治疗MCA205荷瘤小鼠的不利影响，抗CD73，抗PD-L1和5-氟尿嘧啶+奥沙利铂（5FU+OHP）治疗证明了这一点。我们假设改善的反应是肿瘤微环境(TME)驱动的，正如缺乏抗CD73所表明的那样，5FUOHP在体外对细胞系介导的细胞病变作用增强。药效学分析,使用成像质量细胞计数和RNA测序，揭示了细胞毒性T细胞等特定细胞群的显著变化，TME中的B细胞和NK细胞在CT26。转录组分析强调了与免疫反应相关的基因谱的治疗相关调节，NK和T细胞激活，T细胞受体信号传导和干扰素(1型和2型)途径。包含代表组合的各种成分的比较组允许对单个治疗元件的贡献进行去卷积;突出抗CD73抗体介导的关于免疫细胞表现的特定效应，趋化性和骨髓生物学。这些临床前数据反映了腺苷阻断与细胞毒性治疗的互补性，和T细胞检查点抑制，并为支持联合治疗提供了新的机制见解。
