Wang Yubin, Zeng Yilin, Chen Peizhong, Xu Boming, Liu Xiaoqiang, Su Zhijun
Department of Gastroenterology, Quanzhou First Hospital Affiliated to Fujian Medical University Quanzhou 362000, Fujian, China.
Department of Infectious Disease, Quanzhou First Hospital Affiliated to Fujian Medical University Quanzhou 362000, Fujian, China.
Am J Cancer Res. 2025 Aug 15;15(8):3500-3509. doi: 10.62347/ADLH2257. eCollection 2025.
Immunotherapy targeting immune checkpoints such as programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) has emerged as a novel treatment option for various cancers, including colon cancer. However, immune evasion mechanisms can limit the efficacy of cancer immunotherapy. Understanding the regulatory mechanisms of PD-1/PD-L1 expression is therefore critical to enhancing immunotherapeutic outcomes. A previous study demonstrated that the adenosine A1 receptor (Adora1) regulates PD-L1 expression and tumor immune evasion in human melanoma; however, its role in colon cancer and associated immune escape remains poorly defined. To investigate this, we downregulated Adora1 expression in CT26 colon cancer cells using lentiviral transduction of Adora1-targeting shRNA. We assessed Adora1 and PD-L1 expression levels and evaluated cell proliferation in CT26 cells. , we inoculated CT26 cells into mice and monitored tumor growth, immune cell phenotypes, and T cell exhaustion within the tumors. Additionally, we evaluated T cell exhaustion by co-culturing T cells with CT26 cells. While Adora1 knockdown did not impact CT26 cell viability or proliferation , it significantly suppressed tumor growth (P<0.0001). Furthermore, Adora1 downregulation reduced T cell exhaustion (all P=0.0025) by decreasing PD-L1 expression in CT26 cells. Knockdown of Adora1 did not alter Atf3 expression but led to reduced Irf1 expression (P=0.0268), which contributed to the downregulation of PD-L1. Overall, these findings suggest that Adora1 downregulation inhibits immune escape in colon cancer by suppressing PD-L1 expression.
针对程序性死亡-1（PD-1）和程序性死亡配体1（PD-L1）等免疫检查点的免疫疗法已成为包括结肠癌在内的各种癌症的一种新型治疗选择。然而，免疫逃逸机制可能会限制癌症免疫疗法的疗效。因此，了解PD-1/PD-L1表达的调控机制对于提高免疫治疗效果至关重要。先前的一项研究表明，腺苷A1受体（Adora1）调节人类黑色素瘤中PD-L1的表达和肿瘤免疫逃逸；然而，其在结肠癌及相关免疫逃逸中的作用仍不清楚。为了研究这一点，我们使用靶向Adora1的短发夹RNA（shRNA）的慢病毒转导下调CT26结肠癌细胞中Adora1的表达。我们评估了CT26细胞中Adora1和PD-L1的表达水平，并评估了细胞增殖情况。此外，我们将CT26细胞接种到小鼠体内，监测肿瘤生长、免疫细胞表型以及肿瘤内的T细胞耗竭情况。另外，我们通过将T细胞与CT26细胞共培养来评估T细胞耗竭情况。虽然敲低Adora1不影响CT26细胞的活力或增殖，但它显著抑制了肿瘤生长（P<0.0001）。此外，Adora1的下调通过降低CT26细胞中PD-L1的表达减少了T细胞耗竭（所有P=0.0025）。敲低Adora1没有改变Atf3的表达，但导致Irf1表达降低（P=0.0268），这有助于PD-L1的下调。总体而言，这些发现表明，下调Adora1通过抑制PD-L1表达来抑制结肠癌中的免疫逃逸。
