Neuroendocrine Regulation of Stress‐Induced T Cell Dysfunction during Lung Cancer Immunosurveillance via the Kisspeptin/GPR54 Signaling Pathway
Abstract 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) incr...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-05-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202104132 |
| _version_ | 1811234690604990464 |
|---|---|
| author | Su Zhang Fangfei Yu Anran Che Binghe Tan Chenshen Huang Yuxue Chen Xiaohong Liu Qi Huang Wenying Zhang Chengbin Ma Min Qian Mingyao Liu Juliang Qin Bing Du |
| author_facet | Su Zhang Fangfei Yu Anran Che Binghe Tan Chenshen Huang Yuxue Chen Xiaohong Liu Qi Huang Wenying Zhang Chengbin Ma Min Qian Mingyao Liu Juliang Qin Bing Du |
| author_sort | Su Zhang |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-12T11:40:56Z |
| format | Article |
| id | doaj.art-8b00856b0a93453aa5df86cc15715ad0 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-12T11:40:56Z |
| publishDate | 2022-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-8b00856b0a93453aa5df86cc15715ad02022-12-22T03:34:40ZengWileyAdvanced Science2198-38442022-05-01913n/an/a10.1002/advs.202104132Neuroendocrine Regulation of Stress‐Induced T Cell Dysfunction during Lung Cancer Immunosurveillance via the Kisspeptin/GPR54 Signaling PathwaySu Zhang0Fangfei Yu1Anran Che2Binghe Tan3Chenshen Huang4Yuxue Chen5Xiaohong Liu6Qi Huang7Wenying Zhang8Chengbin Ma9Min Qian10Mingyao Liu11Juliang Qin12Bing Du13Shanghai Frontiers Science Center of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences Changning Maternity and Infant Health Hospital East China Normal University Shanghai 200241 ChinaShanghai Frontiers Science Center of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences Changning Maternity and Infant Health Hospital East China Normal University Shanghai 200241 ChinaShanghai Frontiers Science Center of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences Changning Maternity and Infant Health Hospital East China Normal University Shanghai 200241 ChinaBRL Medicine Inc. Shanghai 201109 ChinaDepartment of General Surgery Tongji Hospital School of Medicine Tongji University Shanghai 200065 ChinaShanghai Frontiers Science Center of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences Changning Maternity and Infant Health Hospital East China Normal University Shanghai 200241 ChinaShanghai Frontiers Science Center of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences Changning Maternity and Infant Health Hospital East China Normal University Shanghai 200241 ChinaDepartment of General Surgery Tongji Hospital School of Medicine Tongji University Shanghai 200065 ChinaShanghai Frontiers Science Center of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences Changning Maternity and Infant Health Hospital East China Normal University Shanghai 200241 ChinaShanghai Frontiers Science Center of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences Changning Maternity and Infant Health Hospital East China Normal University Shanghai 200241 ChinaShanghai Frontiers Science Center of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences Changning Maternity and Infant Health Hospital East China Normal University Shanghai 200241 ChinaShanghai Frontiers Science Center of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences Changning Maternity and Infant Health Hospital East China Normal University Shanghai 200241 ChinaShanghai Frontiers Science Center of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences Changning Maternity and Infant Health Hospital East China Normal University Shanghai 200241 ChinaShanghai Frontiers Science Center of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences Changning Maternity and Infant Health Hospital East China Normal University Shanghai 200241 ChinaAbstract 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.https://doi.org/10.1002/advs.202104132ERK5GPR54kisspeptinstressT cell exhaustion |
| spellingShingle | Su Zhang Fangfei Yu Anran Che Binghe Tan Chenshen Huang Yuxue Chen Xiaohong Liu Qi Huang Wenying Zhang Chengbin Ma Min Qian Mingyao Liu Juliang Qin Bing Du Neuroendocrine Regulation of Stress‐Induced T Cell Dysfunction during Lung Cancer Immunosurveillance via the Kisspeptin/GPR54 Signaling Pathway Advanced Science ERK5 GPR54 kisspeptin stress T cell exhaustion |
| title | Neuroendocrine Regulation of Stress‐Induced T Cell Dysfunction during Lung Cancer Immunosurveillance via the Kisspeptin/GPR54 Signaling Pathway |
| title_full | Neuroendocrine Regulation of Stress‐Induced T Cell Dysfunction during Lung Cancer Immunosurveillance via the Kisspeptin/GPR54 Signaling Pathway |
| title_fullStr | Neuroendocrine Regulation of Stress‐Induced T Cell Dysfunction during Lung Cancer Immunosurveillance via the Kisspeptin/GPR54 Signaling Pathway |
| title_full_unstemmed | Neuroendocrine Regulation of Stress‐Induced T Cell Dysfunction during Lung Cancer Immunosurveillance via the Kisspeptin/GPR54 Signaling Pathway |
| title_short | Neuroendocrine Regulation of Stress‐Induced T Cell Dysfunction during Lung Cancer Immunosurveillance via the Kisspeptin/GPR54 Signaling Pathway |
| title_sort | neuroendocrine regulation of stress induced t cell dysfunction during lung cancer immunosurveillance via the kisspeptin gpr54 signaling pathway |
| topic | ERK5 GPR54 kisspeptin stress T cell exhaustion |
| url | https://doi.org/10.1002/advs.202104132 |
| work_keys_str_mv | AT suzhang neuroendocrineregulationofstressinducedtcelldysfunctionduringlungcancerimmunosurveillanceviathekisspeptingpr54signalingpathway AT fangfeiyu neuroendocrineregulationofstressinducedtcelldysfunctionduringlungcancerimmunosurveillanceviathekisspeptingpr54signalingpathway AT anranche neuroendocrineregulationofstressinducedtcelldysfunctionduringlungcancerimmunosurveillanceviathekisspeptingpr54signalingpathway AT binghetan neuroendocrineregulationofstressinducedtcelldysfunctionduringlungcancerimmunosurveillanceviathekisspeptingpr54signalingpathway AT chenshenhuang neuroendocrineregulationofstressinducedtcelldysfunctionduringlungcancerimmunosurveillanceviathekisspeptingpr54signalingpathway AT yuxuechen neuroendocrineregulationofstressinducedtcelldysfunctionduringlungcancerimmunosurveillanceviathekisspeptingpr54signalingpathway AT xiaohongliu neuroendocrineregulationofstressinducedtcelldysfunctionduringlungcancerimmunosurveillanceviathekisspeptingpr54signalingpathway AT qihuang neuroendocrineregulationofstressinducedtcelldysfunctionduringlungcancerimmunosurveillanceviathekisspeptingpr54signalingpathway AT wenyingzhang neuroendocrineregulationofstressinducedtcelldysfunctionduringlungcancerimmunosurveillanceviathekisspeptingpr54signalingpathway AT chengbinma neuroendocrineregulationofstressinducedtcelldysfunctionduringlungcancerimmunosurveillanceviathekisspeptingpr54signalingpathway AT minqian neuroendocrineregulationofstressinducedtcelldysfunctionduringlungcancerimmunosurveillanceviathekisspeptingpr54signalingpathway AT mingyaoliu neuroendocrineregulationofstressinducedtcelldysfunctionduringlungcancerimmunosurveillanceviathekisspeptingpr54signalingpathway AT juliangqin neuroendocrineregulationofstressinducedtcelldysfunctionduringlungcancerimmunosurveillanceviathekisspeptingpr54signalingpathway AT bingdu neuroendocrineregulationofstressinducedtcelldysfunctionduringlungcancerimmunosurveillanceviathekisspeptingpr54signalingpathway |