Open AccessNeuroendocrine Regulation of Stress‐Induced T Cell Dysfunction during Lung Cancer Immunosurveillance via the Kisspeptin/GPR54 Signaling Pathway
Author(s) -
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
Publication year - 2022
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202104132
Subject(s) - kisspeptin , cancer research , immune system , biology , tumor microenvironment , t cell , cd8 , endocrinology , signal transduction , medicine , microbiology and biotechnology , immunology , hormone
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.