Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
Nat Commun. 2022 Jan 10;13(1):97. doi: 10.1038/s41467-021-27658-x.
For many solid tumors, immune checkpoint blockade therapy has become first line treatment, yet a large proportion of patients with immunologically cold tumors do not benefit due to the paucity of tumor infiltrating lymphocytes. Here we show that the orphan G Protein-Coupled Receptor 182 (GPR182) contributes to immunotherapy resistance in cancer via scavenging chemokines that are important for lymphocyte recruitment to tumors. GPR182 is primarily upregulated in melanoma-associated lymphatic endothelial cells (LECs) during tumorigenesis, and this atypical chemokine receptor endocytoses chemokines promiscuously. In GPR182-deficient mice, T cell infiltration into transplanted melanomas increases, leading to enhanced effector T cell function and improved antitumor immunity. Ablation of GPR182 leads to increased intratumoral concentrations of multiple chemokines and thereby sensitizes poorly immunogenic tumors to immune checkpoint blockade and adoptive cellular therapies. CXCR3 blockade reverses the improved antitumor immunity and T cell infiltration characteristic of GPR182-deficient mice. Our study thus identifies GPR182 as an upstream regulator of the CXCL9/CXCL10/CXCR3 axis that limits antitumor immunity and as a potential therapeutic target in immunologically cold tumors.
对于许多实体瘤来说，免疫检查点阻断疗法已成为一线治疗方法，但由于肿瘤浸润淋巴细胞的缺乏，很大一部分免疫冷肿瘤患者无法从中受益。在这里，我们表明孤儿 G 蛋白偶联受体 182（GPR182）通过清除对淋巴细胞募集到肿瘤至关重要的趋化因子，导致癌症的免疫治疗耐药。在肿瘤发生过程中，GPR182 主要在上皮细胞样黑色素瘤相关淋巴管内皮细胞（LEC）中上调，并且这种非典型趋化因子受体随意内吞趋化因子。在 GPR182 缺陷小鼠中，移植黑色素瘤中的 T 细胞浸润增加，导致效应 T 细胞功能增强和抗肿瘤免疫改善。GPR182 的缺失导致多种趋化因子在肿瘤内的浓度增加，从而使免疫原性差的肿瘤对免疫检查点阻断和过继细胞疗法敏感。CXCR3 阻断逆转了 GPR182 缺陷小鼠的抗肿瘤免疫和 T 细胞浸润的改善。因此，我们的研究将 GPR182 鉴定为限制抗肿瘤免疫的 CXCL9/CXCL10/CXCR3 轴的上游调节剂，并将其鉴定为免疫冷肿瘤的潜在治疗靶点。
