Blockade of β-Adrenergic Receptors Improves CD8+ T-cell Priming and Cancer Vaccine Efficacy
Blockade of β-Adrenergic Receptors Improves CD8+ T-cell Priming and Cancer Vaccine Efficacy
复制标题
DOI：
10.1158/2326-6066.cir-18-0833
复制
发表时间：
2019-11-01
影响因子：
10.1
通讯作者：
Feuillet, Vincent
中科院分区：
文献类型：
--
作者：
Daher, Clara;Vimeux, Lene;Feuillet, Vincent
β-肾上腺素能受体（β-AR）信号传导通过直接作用于肿瘤细胞和血管生成而发挥促肿瘤作用。此外，免疫细胞上的β-AR表达影响其产生抗肿瘤免疫应答的能力。然而，β-AR信号传导如何影响抗肿瘤免疫应答仍不清楚。使用基于疫苗的免疫治疗的小鼠模型，我们发现普萘洛尔（一种非选择性β受体阻滞剂）通过提高CD 8（+）T淋巴细胞浸润肿瘤（TIL）的频率，大大提高了抗肿瘤STxBE 7疫苗的疗效。然而，普萘洛尔对CD 8（+）TIL的反应性没有影响，体外实验进一步证实了这一结果，这些细胞对肾上腺素或去甲肾上腺素诱导的AR信号不敏感。相比之下，初始CD 8（+）T细胞活化被β-AR信号强烈抑制，普萘洛尔的有益作用主要发生在肿瘤引流淋巴结中的CD 8（+）T细胞引发期间。我们还证明了初始CD 8（+）T细胞和CD 8（+）TIL对β-AR信号的不同敏感性与β 2-AR表达的强烈下调有关，β 2-AR表达与它们的活化状态有关，因为体外活化的CD 8（+）T细胞的行为与CD 8（+）TIL相似。这些结果表明，β-AR信号转导抑制了抗肿瘤CD 8（+）T细胞应答的初始启动阶段，为在患者中使用临床可用的β-受体阻滞剂以改善癌症免疫治疗提供了理论基础。
beta-Adrenergic receptor (beta-AR) signaling exerts protumoral effects by acting directly on tumor cells and angiogenesis. In addition, beta-AR expression on immune cells affects their ability to mount antitumor immune responses. However, how beta-AR signaling impinges antitumor immune responses is still unclear. Using a mouse model of vaccine-based immunotherapy, we showed that propranolol, a nonselective beta-blocker, strongly improved the efficacy of an antitumor STxBE7 vaccine by enhancing the frequency of CD8(+) T lymphocytes infiltrating the tumor (TIL). However, propranolol had no effect on the reactivity of CD8(+) TILs, a result further strengthened by ex vivo experiments showing that these cells were insensitive to adrenaline-or noradrenaline-induced AR signaling. In contrast, naive CD8(+) T-cell activation was strongly inhibited by beta-AR signaling, and the beneficial effect of propranolol mainly occurred during CD8(+) T-cell priming in the tumor-draining lymph node. We also demonstrated that the differential sensitivity of naive CD8(+) T cells and CD8(+) TILs to beta-AR signaling was linked to a strong downregulation of beta(2)-AR expression related to their activation status, since in vitro-activated CD8(+) T cells behaved similarly to CD8(+) TILs. These results revealed that beta-AR signaling suppresses the initial priming phase of antitumor CD8(+) T-cell responses, providing a rationale to use clinically available beta-blockers in patients to improve cancer immunotherapies.