CD226 overexpression restrains NK92-associated IL-22 and limits an IL-22RA1-pSTAT3-CD155 circuit in the NSCLC tumor microenvironment
- 1The College of Life Sciences, Northwest University
- 2Department of Immunology, School of Basic Medicine, Air Force Medical University
- 3Department of Pulmonary and Critical Care Medicine, Xijing Hospital, Air Force Medical University
Abstract
Background: The immunosuppressive tumor microenvironment (TME) drives tumor immune escape in non-small-cell lung cancer (NSCLC). Tumor-expressed CD155 down-regulates NK-cell CD226; however, whether reduced NK-cell CD226 reciprocally modulates tumor-cell CD155 and the underlying regulatory mechanism remain unclear.
Methods: Public transcriptome datasets GSE32863 and TCGA-LUAD were analyzed. CD226-overexpressing NK92 cells and primary NK cells from CD226-knockout mice were applied in co‑culture systems with NSCLC/LLC tumor cells. Gain-and loss-of-function assays using recombinant IL-22, IL-22 neutralizing antibody and STAT3 siRNA were performed, combined with flow cytometry, RT-qPCR, western blot, ELISA and functional cytotoxicity, proliferation and invasion assays.
Results: LUAD tumor tissues exhibited decreased CD226 but elevated PVR (CD155) and IL-22RA1 expression, correlating with clinical survival outcomes. CD226 overexpression restrained NK-cell-derived IL-22 transcription and secretion. NK-cell-produced IL-22 triggered tumor-cell CD155 upregulation via IL-22RA1-pSTAT3 signaling. CD226-high NK cells displayed stronger anti‑tumor cytotoxicity, while exogenous IL-22 impaired NK-mediated tumor killing. Murine CD226-deficient primary NK cells reproduced this regulatory circuit.
Conclusion: CD226 overexpression restrains NK-cell-derived IL-22 and interrupts an IL-22RA1-pSTAT3-CD155 immune-evasive circuit in NSCLC. This work supports combinatorial NK-cell engineering and IL-22-targeted immunotherapeutic strategies.
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BibTeX
@article{hui2026cd226,
title = {{CD226 overexpression restrains NK92-associated IL-22 and limits an IL-22RA1-pSTAT3-CD155 circuit in the NSCLC tumor microenvironment}},
author = {Ziye Hui and Zichan Guo and Yingjun Peng and Yu’en Zeng and Yongli Hou and Yazhen Wang and Mingjun Ma and Feng Zhao and Dingwen Shi and Lihua Chen},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1973731},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1973731/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - CD226 overexpression restrains NK92-associated IL-22 and limits an IL-22RA1-pSTAT3-CD155 circuit in the NSCLC tumor microenvironment
AU - Ziye Hui
AU - Zichan Guo
AU - Yingjun Peng
AU - Yu’en Zeng
AU - Yongli Hou
AU - Yazhen Wang
AU - Mingjun Ma
AU - Feng Zhao
AU - Dingwen Shi
AU - Lihua Chen
PY - 2026
DA - 2026/11/04
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1973731
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1973731/full
AB - Background: The immunosuppressive tumor microenvironment (TME) drives tumor immune escape in non-small-cell lung cancer (NSCLC). Tumor-expressed CD155 down-regulates NK-cell CD226; however, whether reduced NK-cell CD226 reciprocally modulates tumor-cell CD155 and the underlying regulatory mechanism remain unclear. Methods: Public transcriptome datasets GSE32863 and TCGA-LUAD were analyzed. CD226-overexpressing NK92 cells and primary NK cells from CD226-knockout mice were applied in co‑culture systems with NSCLC/LLC tumor cells. Gain-and loss-of-function assays using recombinant IL-22, IL-22 neutralizing antibody and STAT3 siRNA were performed, combined with flow cytometry, RT-qPCR, western blot, ELISA and functional cytotoxicity, proliferation and invasion assays. Results: LUAD tumor tissues exhibited decreased CD226 but elevated PVR (CD155) and IL-22RA1 expression, correlating with clinical survival outcomes. CD226 overexpression restrained NK-cell-derived IL-22 transcription and secretion. NK-cell-produced IL-22 triggered tumor-cell CD155 upregulation via IL-22RA1-pSTAT3 signaling. CD226-high NK cells displayed stronger anti‑tumor cytotoxicity, while exogenous IL-22 impaired NK-mediated tumor killing. Murine CD226-deficient primary NK cells reproduced this regulatory circuit. Conclusion: CD226 overexpression restrains NK-cell-derived IL-22 and interrupts an IL-22RA1-pSTAT3-CD155 immune-evasive circuit in NSCLC. This work supports combinatorial NK-cell engineering and IL-22-targeted immunotherapeutic strategies.
SN - 1664-3224
ER -