Neuroendocrine Regulation of Stress-Induced T Cell Dysfunction during Lung Cancer Immunosurveillance via the Kisspeptin/GPR54 Signaling Pathway.
Neuroendocrine Regulation of Stress-Induced T Cell Dysfunction during Lung Cancer Immunosurveillance via the Kisspeptin/GPR54 Signaling Pathway.
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通过 Kisspeptin/GPR54 信号通路对肺癌免疫监视过程中应激诱导的 T 细胞功能障碍进行神经内分泌调节
DOI：
10.1002/advs.202104132
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发表时间：
2022-05
期刊：
影响因子：
15.1
通讯作者：
Du, Bing
中科院分区：
文献类型：
--
作者：
Zhang, Su;Yu, Fangfei;Che, Anran;Tan, Binghe;Huang, Chenshen;Chen, Yuxue;Liu, Xiaohong;Huang, Qi;Zhang, Wenying;Ma, Chengbin;Qian, Min;Liu, Mingyao;Qin, Juliang;Du, Bing
越来越多的证据表明，生理应激与癌症的发病率和死亡率高度相关。然而，心理挑战介导肿瘤免疫逃逸的潜在机制尚未得到系统探究。在此，研究表明急性束缚（AR）会提高血浆神经肽激素kisspeptin的水平，以及其受体Gpr54在下丘脑、脾脏和肿瘤浸润T细胞中的表达水平，这表明神经内分泌系统与肿瘤微环境之间存在关联。相应地，给予kisspeptin - 10会显著损害T细胞功能，而在T细胞中敲除Gpr54，无论是否存在AR，都能通过抑制T细胞功能障碍和耗竭来抑制肺肿瘤进展。此外，Gpr54缺陷的OT - 1 T细胞对卵清蛋白（OVA）肽阳性肿瘤表现出更强的抗肿瘤活性。从机制上讲，发现ERK5介导的NR4A1激活对于kisspeptin / GPR54促进的T细胞功能障碍至关重要。同时，XMD8 - 92对ERK5信号通路的药物抑制可通过增强CD8 + T细胞的抗肿瘤功能，显著减缓肿瘤生长。此外，通过CRISPR / Cas9在嵌合抗原受体T细胞（CAR - T细胞）中去除GPR54或ERK5，可增强对前列腺特异性膜抗原（PSMA）阳性和CD19阳性肿瘤细胞的抗肿瘤反应，同时消除T细胞耗竭。综上所述，这些结果表明kisspeptin / GPR54信号通路在应激诱导的肿瘤免疫逃逸中发挥着不可替代的作用。
研究证明，神经内分泌系统通过增强kisspeptin / GPR54信号通路，在生理应激诱导的肿瘤抑制性微环境和免疫逃逸中发挥着不可替代的作用。抑制或去除kisspeptin / GPR54可通过消除T细胞耗竭显著减少肿瘤形成，并增强抗肿瘤免疫反应，这意味着它是T细胞介导免疫治疗的一个有前景的靶点。
Emerging evidence suggests that physiological distress is highly correlated with cancer incidence and mortality. However, the mechanisms underlying psychological challenges‐mediated tumor immune evasion are not systematically explored. Here, it is demonstrated that acute restraint (AR) increases the level of the plasma neuropeptide hormones, kisspeptin, and the expression levels of its receptor, Gpr54, in the hypothalamus, splenic and tumor‐infiltrating T cells, suggesting a correlation between the neuroendocrine system and tumor microenvironment. Accordingly, administration of kisspeptin‐10 significantly impairs T cell function, whereas knockout of Gpr54 in T cells inhibits lung tumor progression by suppressing T cell dysfunction and exhaustion with or without AR. In addition, Gpr54 defective OT‐1 T cells show superior antitumor activity against OVA peptide‐positive tumors. Mechanistically, ERK5‐mediated NR4A1 activation is found to be essential for kisspeptin/GPR54‐facilitated T cell dysfunction. Meanwhile, pharmacological inhibition of ERK5 signaling by XMD8‐92 significantly reduces the tumor growth by enhancing CD8+ T cell antitumor function. Furthermore, depletion of GPR54 or ERK5 by CRISPR/Cas9 in CAR T cells intensifies the antitumor responses to both PSMA+ and CD19+ tumor cells, while eliminating T cell exhaustion. Taken together, these results indicate that kisspeptin/GPR54 signaling plays a nonredundant role in the stress‐induced tumor immune evasion. The neuroendocrine system is demonstrated to play nonredundant roles in physiological distress induced tumor suppressive microenvironment and immune evasion through increasing kisspeptin/GPR54 signaling pathway. And inhibition or depletion of kisspeptin/GPR54 significantly reduced tumor formation by eliminating T cell exhaustion and intensified the antitumor immune responses implying a promising target for T cell mediated immune therapy.
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影响因子：
17.1
作者：
Nilsson MB;Sun H;Diao L;Tong P;Liu D;Li L;Fan Y;Poteete A;Lim SO;Howells K;Haddad V;Gomez D;Tran H;Pena GA;Sequist LV;Yang JC;Wang J;Kim ES;Herbst R;Lee JJ;Hong WK;Wistuba I;Hung MC;Sood AK;Heymach JV
通讯作者：
Heymach JV
影响因子：
32.4
作者：
Jeon, MS;Atfield, A;Penninger, JM
通讯作者：
Penninger, JM
影响因子：
64.8
作者：
Khan, Omar;Giles, Josephine R.;Wherry, E. John
通讯作者：
Wherry, E. John
DOI：
10.1196/annals.1351.006
发表时间：
2006-01-01
期刊：
BASIC AND CLINICAL ASPECTS OF NEUROENDOCRINE IMMUNOLOGY IN RHEUMATIC DISEASES
影响因子：
--
作者：
Calcagni, Emanuele;Elenkov, Ilia
通讯作者：
Elenkov, Ilia
影响因子：
15.9
作者：
Mohammadpour, Hemn;MacDonald, Cameron R.;Repasky, Elizabeth A.
通讯作者：
Repasky, Elizabeth A.