Sensitizing tumors to anti-PD-1 therapy by promoting NK and CD8+ T cells via pharmacological activation of FOXO3.
Sensitizing tumors to anti-PD-1 therapy by promoting NK and CD8+ T cells via pharmacological activation of FOXO3.
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DOI：
10.1136/jitc-2021-002772
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发表时间：
2021-12
影响因子：
10.9
通讯作者：
Hu MC
中科院分区：
文献类型：
--
作者：
Chung YM;Khan PP;Wang H;Tsai WB;Qiao Y;Yu B;Larrick JW;Hu MC
通过阻断程序性死亡-1（PD-1）或其配体（PD-L1）来刺激抗肿瘤免疫是一种很有前途的抗肿瘤治疗方法。然而，许多患者对PD-1/PD-L1阻断反应不佳。对免疫检查点阻断（ICB）的无反应性可能给难以治疗的肿瘤患者的治疗选择带来重大挑战。建立新的治疗方法来减轻患者的ICB无反应性，这是一个未满足的临床需求。在这项研究中，我们研究了低剂量的抗肿瘤药物SN-38或二甲双胍在使对ICB治疗无反应的肿瘤敏感方面的疗效和作用。我们评估了PD-L1和FOXO 3表达之间以及PD-L1和c-Myc或STAT 3表达之间在各种肿瘤患者中的显著病理学关系。我们确定了低剂量SN-38或二甲双胍在同基因肿瘤系统中使无反应的肿瘤对抗PD-1治疗产生反应的有效性。我们破译了SN-38和抗PD-1治疗介导的自然杀伤（NK）或CD 8 + T细胞浸润肿瘤并增强抗肿瘤免疫的新型治疗机制。我们发现，在卵巢、乳腺和肝细胞肿瘤患者中，PD-L1蛋白水平与FOXO 3蛋白水平呈负相关。低剂量SN-38或二甲双胍消除了PD-L1蛋白表达，提高了FOXO 3蛋白水平，并显著提高了同基因小鼠肿瘤模型中的动物存活率。SN-38或二甲双胍通过使NK或CD 8 + T细胞浸润肿瘤微环境（TME）并分泌干扰素-γ和颗粒酶B来致敏对抗PD-1治疗有反应的无反应肿瘤，从而杀死肿瘤。SN-38抑制了控制PD-L1表达的c-Myc和STAT 3蛋白的水平。FOXO 3对于SN 38介导的PD-L1抑制至关重要。在患有指定肿瘤的患者中，PD-L1的表达与c-Myc或STAT 3的表达强制性相关。我们发现SN-38或二甲双胍可以通过FOXO 3激活抑制c-Myc和STAT 3来增强TME中的抗肿瘤免疫力。这些结果可能为改善患者对肿瘤总体免疫治疗的反应提供新的见解。
Stimulating antitumor immunity by blocking programmed death-1 (PD-1) or its ligand (programmed death-ligand 1 (PD-L1) is a promising antitumor therapy. However, numerous patients respond poorly to PD-1/PD-L1 blockade. Unresponsiveness to immune-checkpoint blockade (ICB) can cast significant challenges to the therapeutic options for patients with hard-to-treat tumors. There is an unmet clinical need to establish new therapeutic approaches for mitigating ICB unresponsiveness in patients. In this study, we investigated the efficacy and role of low-dose antineoplastic agent SN-38 or metformin in sensitizing unresponsive tumors to respond to ICB therapy. We assessed the significant pathological relationships between PD-L1 and FOXO3 expression and between PD-L1 and c-Myc or STAT3 expression in patients with various tumors. We determined the efficacy of low-dose SN-38 or metformin in sensitizing unresponsive tumors to respond to anti-PD-1 therapy in a syngeneic tumor system. We deciphered novel therapeutic mechanisms underlying the SN-38 and anti-PD-1 therapy-mediated engagement of natural killer (NK) or CD8+ T cells to infiltrate tumors and boost antitumor immunity. We showed that PD-L1 protein level was inversely associated with FOXO3 protein level in patients with ovarian, breast, and hepatocellular tumors. Low-dose SN-38 or metformin abrogated PD-L1 protein expression, promoted FOXO3 protein level, and significantly increased the animal survival rate in syngeneic mouse tumor models. SN-38 or metformin sensitized unresponsive tumors responding to anti-PD-1 therapy by engaging NK or CD8+ T cells to infiltrate the tumor microenvironment (TME) and secret interferon-γ and granzyme B to kill tumors. SN-38 suppressed the levels of c-Myc and STAT3 proteins, which controlled PD-L1 expression. FOXO3 was essential for SN38-mediated PD-L1 suppression. The expression of PD-L1 was compellingly linked to that of c-Myc or STAT3 in patients with the indicated tumors. We show that SN-38 or metformin can boost antitumor immunity in the TME by inhibiting c-Myc and STAT3 through FOXO3 activation. These results may provide novel insight into ameliorating patient response to overarching immunotherapy for tumors.
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DOI：
10.1126/science.aac9935
发表时间：
2016-04-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Casey SC;Tong L;Li Y;Do R;Walz S;Fitzgerald KN;Gouw AM;Baylot V;Gütgemann I;Eilers M;Felsher DW
通讯作者：
Felsher DW
影响因子：
11.2
作者：
Barsoum, Ivraym B.;Smallwood, Chelsea A.;Graham, Charles H.
通讯作者：
Graham, Charles H.
影响因子：
64.5
作者：
Gauthier, Laurent;Morel, Ariane;Vivier, Eric
通讯作者：
Vivier, Eric
影响因子：
64.5
作者：
Barrow AD;Edeling MA;Trifonov V;Luo J;Goyal P;Bohl B;Bando JK;Kim AH;Walker J;Andahazy M;Bugatti M;Melocchi L;Vermi W;Fremont DH;Cox S;Cella M;Schmedt C;Colonna M
通讯作者：
Colonna M
影响因子：
64.5
作者：
Gao, Jianjun;Shi, Lewis Zhichang;Zhao, Hao;Chen, Jianfeng;Xiong, Liangwen;He, Qiuming;Chen, Tenghui;Roszik, Jason;Bernatchez, Chantale;Woodman, Scott E.;Chen, Pei-Ling;Hwu, Patrick;Allison, James P.;Futreal, Andrew;Wargo, Jennifer A.;Sharma, Padmanee
通讯作者：
Sharma, Padmanee