当前位置: X-MOL 学术Nat. Commun. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Activation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunity
Nature Communications ( IF 14.7 ) Pub Date : 2023-09-15 , DOI: 10.1038/s41467-023-41101-3
Yazhong Cui 1, 2 , Yang Miao 2, 3 , Longzhi Cao 1, 2 , Lifang Guo 4 , Yue Cui 2, 5 , Chuanzhe Yan 2, 6 , Zhi Zeng 1, 2 , Mo Xu 1, 2, 7 , Ting Han 1, 2, 7
Affiliation  

Inhibition of T cell infiltration dampens antitumor immunity and causes resistance to immune checkpoint blockade (ICB) therapy. By in vivo CRISPR screening in B16F10 melanoma in female mice, here we report that loss of melanocortin-1 receptor (MC1R) in melanoma cells activates antitumor T cell response and overcomes resistance to ICB. Depletion of MC1R from another melanocytic melanoma model HCmel1274 also enhances ICB efficacy. By activating the GNAS-PKA axis, MC1R inhibits interferon-gamma induced CXCL9/10/11 transcription, thus impairing T cell infiltration into the tumor microenvironment. In human melanomas, high MC1R expression correlates with reduced CXCL9/10/11 expression, impaired T cell infiltration, and poor patient prognosis. Whereas MC1R activation is restricted to melanoma, GNAS activation by hotspot mutations is observed across diverse cancer types and is associated with reduced CXCL9/10/11 expression. Our study implicates MC1R as a melanoma immunotherapy target and suggests GNAS-PKA signaling as a pan-cancer oncogenic pathway inhibiting antitumor T cell response.



中文翻译:

黑色素瘤细胞中 melanocortin-1 受体信号的激活会损害 T 细胞浸润,从而抑制抗肿瘤免疫

T 细胞浸润的抑制会抑制抗肿瘤免疫并导致对免疫检查点阻断 (ICB) 疗法的抵抗。通过对雌性小鼠 B16F10 黑色素瘤进行体内 CRISPR 筛选,我们报告黑色素瘤细胞中黑皮质素-1 受体 (MC1R) 的缺失可激活抗肿瘤 T 细胞反应并克服对 ICB 的耐药性。另一种黑色素细胞黑色素瘤模型 HCmel1274 中 MC1R 的消耗也增强了 ICB 功效。通过激活 GNAS-PKA 轴,MC1R 抑制干扰素 γ 诱导的CXCL9 / 10 / 11转录,从而损害 T 细胞浸润到肿瘤微环境中。在人类黑色素瘤中, MC1R高表达与CXCL9 / 10 / 11表达减少、T 细胞浸润受损和患者预后不良相关。MC1R 激活仅限于黑色素瘤,而热点突变引起的 GNAS 激活则在多种癌症类型中观察到,并且与CXCL9 / 10 / 11表达减少相关。我们的研究表明 MC1R 作为黑色素瘤免疫治疗靶点,并表明 GNAS-PKA 信号传导作为抑制抗肿瘤 T 细胞反应的泛癌致癌途径。

更新日期:2023-09-16
down
wechat
bug