Inhibitors of the CD73-adenosinergic checkpoint as promising combinatory agents for conventional and advanced cancer immunotherapy.
Inhibitors of the CD73-adenosinergic checkpoint as promising combinatory agents for conventional and advanced cancer immunotherapy.
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DOI：
10.3389/fimmu.2023.1212209
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发表时间：
2023
影响因子：
7.3
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中科院分区：
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除了PD-1/PD-L1和CTLA-4外，细胞表面酶CD73被认为是一种关键的非冗余免疫检查点(IC)。CD73产生胞外腺苷(EADO)，不仅通过腺苷受体(AR)A2AR抑制T细胞的抗肿瘤活性，而且通过A2BR增强肿瘤相关成纤维细胞和髓系细胞的免疫抑制功能。临床前研究表明，在许多实体肿瘤的实验模型中，抑制CD73-腺苷能通路无论是作为单一治疗，还是更有效地与PD-1/PD-L1或CTLA-4 IC阻断联合使用，都可以提高抗肿瘤免疫能力和肿瘤控制。因此，https://clinicaltrials.gov.上目前列出了大约50项针对CD73腺苷能IC的正在进行的I/II期临床试验大多数列出的试验单独使用CD73抑制剂或抗CD73抗体，与A2AR拮抗剂和/或PD-1/PD-L1阻断联合使用。最近的证据表明，CD73、A2AR和A2BR在肿瘤微环境中的分布是不均匀的，这种分布影响CD73-腺苷能IC的功能。这些新的见解对针对这一重要IC的最佳有效、精心定制的治疗靶向方法具有重要意义。在这篇简短的综述中，我们简要讨论了CD73/EADO介导的免疫抑制在肿瘤进展和治疗中的细胞和分子机制。我们包括有关肿瘤模型中治疗性CD73-EADO阻断的临床前数据，以及针对CD73-腺苷能IC使用或不使用PD-1/PD-L1抑制剂的已完成试验的可用临床数据，并讨论对癌症患者的最佳治疗结果具有潜在重要性的因素。
The cell surface enzyme CD73 is increasingly appreciated as a pivotal non-redundant immune checkpoint (IC) in addition to PD-1/PD-L1 and CTLA-4. CD73 produces extracellular adenosine (eADO), which not only inhibits antitumor T cell activity via the adenosine receptor (AR) A2AR, but also enhances the immune inhibitory function of cancer-associated fibroblasts and myeloid cells via A2BR. Preclinical studies show that inhibition of the CD73-adenosinergic pathway in experimental models of many solid tumors either as a monotherapy or, more effectively, in combination with PD-1/PD-L1 or CTLA-4 IC blockades, improves antitumor immunity and tumor control. Consequently, approximately 50 ongoing phase I/II clinical trials targeting the CD73-adenosinergic IC are currently listed on https://clinicaltrials.gov. Most of the listed trials employ CD73 inhibitors or anti-CD73 antibodies alone, in combination with A2AR antagonists, and/or with PD-1/PD-L1 blockade. Recent evidence suggests that the distribution of CD73, A2AR and A2BR in tumor microenvironments (TME) is heterogeneous, and this distribution affects CD73-adenosinergic IC function. The new insights have implications for the optimally effective, carefully tailored approaches to therapeutic targeting of this essential IC. In the mini-review, we briefly discuss the cellular and molecular mechanisms of CD73/eADO-mediated immunosuppression during tumor progression and therapy in the spatial context of the TME. We include preclinical data regarding therapeutic CD73-eADO blockade in tumor models as well as available clinical data from completed trials that targeted CD73-adenosinergic IC with or without PD-1/PD-L1 inhibitors and discuss factors that are potentially important for optimal therapeutic outcomes in cancer patients.