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PDE4D/cAMP/IL-23 axis determines the immunotherapy efficacy of lung adenocarcinoma via activating the IL-9 autocrine loop of cytotoxic T lymphocytes.
- Source :
-
Cancer letters [Cancer Lett] 2023 Jul 01; Vol. 565, pp. 216224. Date of Electronic Publication: 2023 May 16. - Publication Year :
- 2023
-
Abstract
- Although immunotherapy has changed the prognosis of many advanced malignancies including lung adenocarcinoma (LUAD), many patients are insensitive to the drugs, with the mechanisms yet to be elucidated. Herein, we identified PDE4D as an immunotherapy efficacy-related gene through bioinformatics screening. By using a co-culture system of LUAD cells and tumor-cell-specific CD8 <superscript>+</superscript> T cells, a functional PDE4D/cAMP/IL-23 axis was further revealed in LUAD cells. Fluorescent multiplex immunohistochemistry analysis of patient-derived samples and the in vivo mouse LUAD xenograft tumors revealed not only the colocalization of IL-23 and CD8 <superscript>+</superscript> T cells but also the immune potentiating effect of IL-23 on cytotoxic T lymphocytes (CTLs) in LUAD tissues. Through transcriptome sequencing and functional validations, IL-23 was proven to up-regulate IL-9 expression in CTLs via activating the NF-κB signaling, leading to elevated productions of immune effector molecules and enhanced efficacy of antitumor immunotherapy. Interestingly, an autocrine loop of IL-9 was also uncovered during this process. In conclusion, PDE4D/cAMP/IL-23 axis determines the immunotherapy efficacy of human LUAD. This effect is mediated by the activation of an NF-κB-dependent IL-9 autocrine loop in CTLs.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Humans
Mice
Animals
T-Lymphocytes, Cytotoxic
Interleukin-9
NF-kappa B metabolism
CD8-Positive T-Lymphocytes metabolism
Immunotherapy
Interleukin-23
Cyclic Nucleotide Phosphodiesterases, Type 4 genetics
Cyclic Nucleotide Phosphodiesterases, Type 4 metabolism
Adenocarcinoma of Lung genetics
Adenocarcinoma of Lung therapy
Adenocarcinoma of Lung pathology
Lung Neoplasms genetics
Lung Neoplasms therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7980
- Volume :
- 565
- Database :
- MEDLINE
- Journal :
- Cancer letters
- Publication Type :
- Academic Journal
- Accession number :
- 37196909
- Full Text :
- https://doi.org/10.1016/j.canlet.2023.216224