PDF(Pubmed)
Abstract：
Adenosine triphosphate (ATP) represents a danger signal that accumulates in injured tissues, in inflammatory sites, and in the tumor microenvironment. ATP promotes tumor growth but also anti-tumor immune responses notably via the P2X7 receptor. ATP can also be catabolized by CD39 and CD73 ecto-enzymes into immunosuppressive adenosine. P2X7, CD39 and CD73 have attracted much interest in cancer as targets offering the potential to unleash anti-tumor immune responses. These membrane proteins represent novel purinergic checkpoints that can be targeted by small drugs or biologics. Here, we investigated nanobody-based biologics targeting mainly P2X7, but also CD73, alone or in combination therapies. Blocking P2X7 inhibited tumor growth and improved survival of mice in cancer models that express P2X7. P2X7-potentiation by a nanobody-based biologic was not effective alone to control tumor growth but enhanced tumor control and immune responses when used in combination with oxaliplatin chemotherapy. We also evaluated a bi-specific nanobody-based biologic that targets PD-L1 and CD73. This novel nanobody-based biologic exerted a potent anti-tumor effect, promoting tumor rejection and improving survival of mice in two tumor models. Hence, this study highlights the importance of purinergic checkpoints in tumor control and open new avenues for nanobody-based biologics that may be further exploited in the treatment of cancer.
摘要：
三磷酸腺苷（ATP）代表了一种在受损组织中积累的危险信号，在炎症部位，在肿瘤微环境中。ATP尤其通过P2X7受体促进肿瘤生长以及抗肿瘤免疫应答。ATP也可以被CD39和CD73的胞外酶分解代谢成免疫抑制性腺苷。P2X7、CD39和CD73作为提供释放抗肿瘤免疫应答潜力的靶标已经引起了对癌症的极大兴趣。这些膜蛋白代表了新的嘌呤能检查点，可以被小药物或生物制剂靶向。这里,我们研究了基于纳米抗体的生物制剂，主要靶向P2X7，但也有CD73，单独或联合治疗。在表达P2X7的癌症模型中,阻断P2X7抑制肿瘤生长并改善小鼠的存活率。基于纳米抗体的生物制剂的P2X7增强单独控制肿瘤生长并不有效，但与奥沙利铂化疗联合使用时可增强肿瘤控制和免疫反应。我们还评估了一种靶向PD-L1和CD73的基于双特异性纳米抗体的生物制剂。这种基于纳米抗体的新型生物制剂发挥了强大的抗肿瘤作用，在两种肿瘤模型中促进肿瘤排斥并改善小鼠的存活率。因此，这项研究强调了嘌呤能检查点在肿瘤控制中的重要性,并为基于纳米抗体的生物制剂开辟了新的途径,可进一步用于癌症治疗.
