Immunotherapy based on immunecheckpoint blockade (ICB) using antibodies induces rejection of tumours and brings clinical benefit in patients with various cancer types¹. However, tumours often resist immune rejection. Ongoing efforts trying to increase tumour response rates are based on combinations of ICB with compounds that aim to reduce immunosuppression in the tumour microenvironment but usually have little effect when used as monotherapies^2,3. Here we show that agonists of α2-adrenergic receptors (α2-AR) have very strong anti-tumour activity when used as monotherapies in multiple immunocompetent tumour models, including ICB-resistant models, but not in immunodeficient models. We also observed marked effects in human tumour xenografts implanted in mice reconstituted with human lymphocytes. The anti-tumour effects of α2-AR agonists were reverted by α2-AR antagonists, and were absent in Adra2a-knockout (encoding α2a-AR) mice, demonstrating on-target action exerted on host cells, not tumour cells. Tumours from treated mice contained increased infiltrating T lymphocytes and reduced myeloid suppressor cells, which were more apoptotic. Single-cell RNA-sequencing analysis revealed upregulation of innate and adaptive immune response pathways in macrophages and T cells. To exert their anti-tumour effects, α2-AR agonists required CD4⁺ T lymphocytes, CD8⁺ T lymphocytes and macrophages. Reconstitution studies in Adra2a-knockout mice indicated that the agonists acted directly on macrophages, increasing their ability to stimulate T lymphocytes. Our results indicate that α2-AR agonists, some of which are available clinically, could substantially improve the clinical efficacy of cancer immunotherapy.

基于使用抗体的免疫检查点阻断 (ICB) 的免疫疗法可诱导肿瘤排斥，并为患有各种癌症类型的患者带来临床益处¹。然而，肿瘤常常抵抗免疫排斥。持续努力提高肿瘤反应率的基础是 ICB 与旨在减少肿瘤微环境中免疫抑制的化合物的组合，但作为单一疗法使用时通常效果甚微^2,3。在这里，我们表明，α2-肾上腺素受体（α2-AR）激动剂在多种免疫活性肿瘤模型（包括 ICB 耐药模型）中用作单一疗法时具有非常强的抗肿瘤活性，但在免疫缺陷模型中则不然。我们还观察到植入用人类淋巴细胞重建的小鼠体内的人类肿瘤异种移植物的显着效果。α2-AR 激动剂的抗肿瘤作用可被 α2-AR 拮抗剂逆转，并且在Adra2a中不存在-基因敲除（编码α2a-AR）小鼠，证明对宿主细胞而不是肿瘤细胞发挥靶向作用。接受治疗的小鼠肿瘤中浸润性 T 淋巴细胞增多，骨髓抑制细胞减少，且凋亡率更高。单细胞 RNA 测序分析揭示了巨噬细胞和 T 细胞中先天性和适应性免疫反应途径的上调。为了发挥其抗肿瘤作用，α2-AR激动剂需要CD4 ⁺ T淋巴细胞、CD8 ⁺ T淋巴细胞和巨噬细胞。Adra2a中的重构研究-基因敲除小鼠表明激动剂直接作用于巨噬细胞，增加其刺激T淋巴细胞的能力。我们的结果表明，α2-AR激动剂（其中一些已在临床上使用）可以显着提高癌症免疫治疗的临床疗效。