CD73, an ecto-5'-nucleotidase (NT5E), serves as an immune checkpoint by generating adenosine (ADO), which suppresses immune activation through the A2A receptor. Elevated CD73 levels in tumor tissues correlate with poor clinical outcomes. However, the crucial source of CD73 activity within the tumor microenvironment remains unspecified. Here, we demonstrate that cancer-associated fibroblasts (CAFs) constitute the prominent CD73hi population in human colorectal cancers (CRCs) and two CD73- murine tumor models, including a modified CRC. Clinically, high CAF abundancy in CRC tissues correlates strongly with elevated CD73 activity and poor prognosis. Mechanistically, CAF-CD73 expression is enhanced via an ADO-A2B receptor-mediated feedforward circuit triggered by tumor cell death, which enforces the CD73-checkpoint. Simultaneous inhibition of A2A and A2B pathways with CD73-neutralization synergistically enhances antitumor immunity in CAF-rich tumors. Therefore, the strategic and effective targeting of both the A2B-mediated ADO-CAF-CD73 feedforward circuit and A2A-mediated immune suppression is crucial for improving therapeutic outcomes.

中文翻译：

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由A2B介导的前馈回路增强的与癌症相关的成纤维细胞上的CD73增强了免疫检查点。

CD73，一种外5'-核苷酸酶（NT5E），通过产生腺苷（ADO）来充当免疫检查点，ADO抑制通过A2A受体的免疫激活。肿瘤组织中CD73水平升高与不良的临床预后相关。但是，肿瘤微环境中CD73活性的关键来源仍然不确定。在这里，我们证明了与癌症相关的成纤维细胞（CAF）构成了人类结直肠癌（CRC）和两个CD73-鼠类肿瘤模型（包括改良的CRC）中主要的CD73hi种群。临床上，CRC组织中高CAF丰度与CD73活性升高和预后不良密切相关。从机理上讲，通过由肿瘤细胞死亡触发的ADO-A2B受体介导的前馈回路，CAF-CD73的表达得以增强，从而增强了CD73-检查点。CD73中和同时抑制A2A和A2B途径可协同增强富含CAF的肿瘤的抗肿瘤免疫力。因此，A2B介导的ADO-CAF-CD73前馈回路和A2A介导的免疫抑制的战略和有效靶向对于改善治疗效果至关重要。