Propranolol inhibit tumor growth through reducing T cell exhaustion. Propranolol inhibit tumor growth through reducing T cell exhaustion

Recently, targeting or reinvigorating exhausted T cells have become the focus of cancer immunotherapy. Propranolol, a non-selection β1 and β2 adrenergic receptor blocker, or in combination with other drug, can inhibit the development of various tumors. Additionally, β2-adrenergic receptor (ADRB2) signaling suppresses the effector function of CD8+ T cell. However, whether propranolol plays an anti-tumor role by directly inhibiting T cell exhaustion remains unclear. In this study, we found that Propranolol significantly inhibited the development of AOM/DSS-induced colorectal cancer, and reduced the exhaustion of infiltrating T cell in colorectal cancer tissues. The anti-tumor effect of propranolol was further determined by CT26, B16F10, and MC38 subcutaneous tumor models in vivo. Cell viability analysis showed that Propranolol concentration below 40 μM had no effect on the viability of CT26 colorectal cancer cells. We also found that propranolol treatment did not inhibit the growth of tumors in BALB/c nude mice. The above results indicated that Propranolol relied on T cells to exert its anti-tumor effects. Bioinformatics analysis highlighted that ADRB2 was positive correlated with T cell exhaustion signature in colon adenocarcinoma, pancreatic adenocarcinoma, testicular germ cell tumors, and glioblastoma multiforme patients using the website of GEPIA. Accordingly, Propranolol directly inhibited T cells exhaustion, and increased IFN-γ secretion of CD4+ and CD8+ T cells in vitro. Collectively, propranolol plays anti-tumor role by directly inhibiting T cell exhaustion. Overall design: CT26 subcutaneous tumors mRNA profiles of Control and Propranolol tretment mice were generated by deep sequencing, in duplicate.

近年来，靶向或重振耗竭T细胞已成为癌症免疫治疗的研究热点。普萘洛尔作为一种非选择性β1和β2肾上腺素能受体阻滞剂，单独或与其他药物联合使用，可抑制多种肿瘤的发生发展。此外，β2肾上腺素能受体（β2-adrenergic receptor, ADRB2）信号通路可抑制CD8+ T细胞的效应功能。然而，普萘洛尔是否通过直接抑制T细胞耗竭发挥抗肿瘤作用，目前尚不清楚。本研究发现，普萘洛尔可显著抑制AOM/DSS诱导的结直肠癌发生，并降低结直肠癌组织中浸润T细胞的耗竭程度。进一步通过CT26、B16F10及MC38皮下移植瘤模型在体内验证了普萘洛尔的抗肿瘤作用。细胞活力检测结果显示，浓度低于40 μM的普萘洛尔对CT26结直肠癌细胞的活力无显著影响。同时发现，普萘洛尔处理无法抑制BALB/c裸小鼠体内的肿瘤生长。上述结果表明，普萘洛尔需依赖T细胞才能发挥抗肿瘤功效。借助GEPIA数据库进行的生物信息学分析显示，在结肠腺癌、胰腺腺癌、睾丸生殖细胞肿瘤及多形性胶质母细胞瘤患者中，ADRB2的表达水平与T细胞耗竭特征呈正相关。据此，体外实验证实普萘洛尔可直接抑制T细胞耗竭，并提升CD4+及CD8+ T细胞的干扰素γ（Interferon-γ, IFN-γ）分泌水平。综上，普萘洛尔通过直接抑制T细胞耗竭发挥抗肿瘤作用。实验整体设计：对对照组及普萘洛尔处理组小鼠的CT26皮下移植瘤组织进行双份深度测序，以获取其mRNA表达谱。