Antibody-mediated blockade of the IL23 receptor destabilizes intratumoral regulatory T cells and enhances immunotherapy.
Antibody-mediated blockade of the IL23 receptor destabilizes intratumoral regulatory T cells and enhances immunotherapy.
复制标题
抗体介导的IL23受体阻断使肿瘤内调节性T细胞不稳定并增强免疫治疗。
DOI：
10.1073/pnas.2200757119
复制
发表时间：
2022-05-03
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
调节性T细胞依赖于活跃的过程来维持肿瘤内的抑制性表型，导致肿瘤负荷增加和癌症结局恶化。在这里，我们报告了一种通过破坏白细胞介素23受体的表达来干扰调节性T细胞（Treg）稳定性的途径。这种方法增加了Treg对白细胞介素12的反应性，导致γ-干扰素的产生增加和更有效的抗肿瘤免疫应答。通过白细胞介素23受体和糖皮质激素诱导的TNFR相关蛋白受体使Treg不稳定的独立途径的组合参与对Treg表型具有协同影响并促进抗肿瘤免疫应答。这些发现扩展了我们对调节性T细胞生物学的理解，并为癌症免疫治疗提供了工具。调节性T细胞（Treg）可以阻碍抗肿瘤免疫，目前是有效癌症免疫治疗的主要障碍。靶向肿瘤浸润性调节性Treg，同时保留系统性Treg代表了解决该问题的最佳方法。在这里，我们提供的证据表明，白细胞介素23受体（IL 23 R）表达的肿瘤浸润性调节性T细胞促进抑制活性。IL 23 R的破坏导致不稳定的Treg对IL 12细胞因子的反应性增加，γ-干扰素的产生和抑制肿瘤生长的CD 8 T细胞的募集。由于由IL 23 R阻断启动的Treg去稳定化途径与糖皮质激素诱导的TNFR相关蛋白（GITR）活化偶联的去稳定化途径不同且独立，因此我们检查了两种去稳定化途径的协同诱导对抗肿瘤免疫应答的影响。用MC 38肿瘤接种的小鼠的组合GITR和IL 23 R抗体处理导致稳健和协同的抗肿瘤应答。这些发现表明，独立的Treg去稳定化途径的描绘可以允许改进用于开发癌症的组合免疫疗法的方法。
Regulatory T cells rely on active processes to maintain a suppressive phenotype inside a tumor, leading to increased tumor burden and worse cancer outcomes. Here, we report a pathway to interfere with regulatory T cell (Treg) stability by disrupting the expression of the interleukin 23 receptor. This approach increases Treg responsiveness to interleukin 12, leading to increased production of gamma-interferon and more efficient antitumor immune responses. The combined engagement of independent pathways to destabilize Treg through the interleukin 23 receptor and the glucocorticoid-induced TNFR-related protein receptor has a synergistic impact on the Treg phenotype and promotes antitumor immune responses. These findings expand our understanding of regulatory T-cell biology and offer tools for cancer immunotherapy. Regulatory T cells (Treg) can impede antitumor immunity and currently represent a major obstacle to effective cancer immunotherapy. Targeting tumor-infiltrating regulatory Treg while sparing systemic Treg represents an optimal approach to this problem. Here, we provide evidence that the interleukin 23 receptor (IL23R) expressed by tumor-infiltrating Treg promotes suppressive activity. Disruption of the IL23R results in increased responsiveness of destabilized Treg to the IL12 cytokine, the production of γ-interferon, and the recruitment of CD8 T cells that inhibit tumor growth. Since the Treg destabilization pathway that is initiated by IL23R blockade is distinct and independent from the destabilization pathway coupled to glucocorticoid-induced TNFR-related protein (GITR) activation, we examined the impact of the coordinate induction of the two destabilization pathways on antitumor immune responses. Combined GITR and IL23R antibody treatment of mice inoculated with MC38 tumors resulted in robust and synergistic antitumor responses. These findings indicate that the delineation of independent Treg destabilization pathways may allow improved approaches to the development of combination immunotherapy for cancers.
登录
查看更多内容
影响因子：
8
作者：
Chan, I. H.;Jain, R.;LaFace, D.
通讯作者：
LaFace, D.
影响因子：
--
作者：
Nowicka, Malgorzata;Krieg, Carsten;Robinson, Mark D
通讯作者：
Robinson, Mark D
影响因子：
82.9
作者：
Zappasodi, Roberta;Sirard, Cynthia;Merghoub, Taha
通讯作者：
Merghoub, Taha
DOI：
10.1126/science.aad0616
发表时间：
2015-10-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kim HJ;Barnitz RA;Kreslavsky T;Brown FD;Moffett H;Lemieux ME;Kaygusuz Y;Meissner T;Holderried TA;Chan S;Kastner P;Haining WN;Cantor H
通讯作者：
Cantor H
影响因子：
8.8
作者：
Wang, Lei;Shen, Erxia;Leavenworth, Jianmei W.
通讯作者：
Leavenworth, Jianmei W.