Department of Neurosurgery, Duke University Medical School, Durham, NC 27710.
Department of Neurosurgery, Duke University Medical School, Durham, NC 27710
J Immunol. 2021 Mar 15;206(6):1385-1394. doi: 10.4049/jimmunol.2000792. Epub 2021 Jan 27.
Crosstalk between costimulatory and coinhibitory ligands are a prominent node of immune cell regulation. Mounting evidence points toward a critical role for CD155, the poliovirus receptor, in suppressing T cell function, particularly in cancer. However, relative to other known costimulatory/coinhibitory ligands (e.g., CD86, CD80, PD-L1), the physiological functions of CD155 and the mechanisms controlling its expression remain unclear. We discovered that CD155 expression is coregulated with PD-L1 on tumor-associated macrophages, is transcriptionally regulated by persistently active aryl hydrocarbon receptor (AhR), and can be targeted for suppression via AhR inhibition in vivo. Therapeutic inhibition of AhR reversed tumor immunosuppression in an immune competent murine tumor model, and markers of AhR activity were highly correlated with tumor-associated macrophage markers in human glioblastomas. Thus, CD155 functions within a broader, AhR-controlled macrophage activation phenotype that can be targeted to reverse tumor immunosuppression.
共刺激和共抑制配体之间的串扰是免疫细胞调节的一个重要节点。越来越多的证据表明，脊髓灰质炎病毒受体 CD155 在抑制 T 细胞功能方面起着关键作用，特别是在癌症中。然而，与其他已知的共刺激/共抑制配体（如 CD86、CD80、PD-L1）相比，CD155 的生理功能及其表达调控机制尚不清楚。我们发现 CD155 的表达与肿瘤相关巨噬细胞上的 PD-L1 共同调节，受持续激活的芳烃受体 (AhR) 转录调控，并可通过体内 AhR 抑制进行抑制。AhR 的治疗性抑制可逆转免疫功能正常的小鼠肿瘤模型中的肿瘤免疫抑制，并且 AhR 活性标志物与人类胶质母细胞瘤中的肿瘤相关巨噬细胞标志物高度相关。因此，CD155 在更广泛的 AhR 控制的巨噬细胞激活表型中发挥作用，可通过该表型来逆转肿瘤免疫抑制。
