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Article

Irradiation Suppresses IFNγ-Mediated PD-L1 and MCL1 Expression in EGFR-Positive Lung Cancer to Augment CD8+ T Cells Cytotoxicity

1
Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Linkou 333, Taiwan
2
Division of Hematology and Oncology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei 104, Taiwan
3
Laboratory of Good Clinical Research Center, Department of Medical Research, Mackay Memorial Hospital, Tamsui District, New Taipei City 251, Taiwan
4
Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan
5
Division of Gastroenterology, Cheng Hsin General Hospital, Taipei 112, Taiwan
6
Graduate Institute of Medical Sciences, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
7
Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan 325, Taiwan
*
Author to whom correspondence should be addressed.
Equal contribution.
Academic Editor: Lucas Treps
Cells 2021, 10(10), 2515; https://doi.org/10.3390/cells10102515
Received: 16 August 2021 / Revised: 20 September 2021 / Accepted: 20 September 2021 / Published: 23 September 2021
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Lung Cancers)
Tumor cells express immune checkpoints to exhaust CD8+ T cells. Irradiation damages tumor cells and augments tumor immunotherapy in clinical applications. However, the radiotherapy-mediated molecular mechanism affecting CD8+ T cell activity remains elusive. We aimed to uncover the mechanism of radiotherapy augmenting cytotoxic CD8+ T cells in non-small-cell lung cancer (NSCLC). EGFR-positive NSCLC cell lines were co-cultured with CD8+ T cells from healthy volunteers. Tumor cell viability and apoptosis were consequently measured. IFNγ was identified secreted by CD8+ T cells and PBMCs. Therefore, RNAseq was used to screen the IFNγ-mediated gene expression in A549 cells. The irradiation effect to IFNγ-mediated gene expression was investigated using qPCR and western blots. We found that the co-culture of tumor cells stimulated the increase of granzyme B and IFNγ in CD8+ T, but A549 exhibited resistance against CD8+ T cytotoxicity compared to HCC827. Irradiation inhibited A549 proliferation and enhanced apoptosis, augmenting PBMCs-mediated cytotoxicity against A549. We found that IFNγ simultaneously increased phosphorylation on STAT1 and STAT3 in EGFR-positive lung cancer, resulting in overexpression of PD-L1 (p < 0.05). In RNAseq analysis, MCL1 was identified and increased by the IFNγ-STAT3 axis (p < 0.05). We demonstrated that irradiation specifically inhibited phosphorylation on STAT1 and STAT3 in IFNγ-treated A549, resulting in reductions of PD-L1 and MCL1 (both p < 0.05). Moreover, knockdowns of STAT3 and MCL1 increased the PBMCs-mediated anti-A549 effect. This study demonstrated that A549 expressed MCL1 to resist CD8+ T cell-mediated tumor apoptosis. In addition, we found that irradiation suppressed IFNγ-mediated STAT3 phosphorylation and PD-L1 and MCL1 expression, revealing a potential mechanism of radiotherapy augmenting immune surveillance. View Full-Text
Keywords: non-small-cell lung cancer; STAT1; STAT3; PD-L1; MCL1; CD8+ T cells; irradiation; radiotherapy non-small-cell lung cancer; STAT1; STAT3; PD-L1; MCL1; CD8+ T cells; irradiation; radiotherapy
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MDPI and ACS Style

Wang, C.-I.; Chang, Y.-F.; Sie, Z.-L.; Ho, A.-S.; Chang, J.-S.; Peng, C.-L.; Cheng, C.-C. Irradiation Suppresses IFNγ-Mediated PD-L1 and MCL1 Expression in EGFR-Positive Lung Cancer to Augment CD8+ T Cells Cytotoxicity. Cells 2021, 10, 2515. https://doi.org/10.3390/cells10102515

AMA Style

Wang C-I, Chang Y-F, Sie Z-L, Ho A-S, Chang J-S, Peng C-L, Cheng C-C. Irradiation Suppresses IFNγ-Mediated PD-L1 and MCL1 Expression in EGFR-Positive Lung Cancer to Augment CD8+ T Cells Cytotoxicity. Cells. 2021; 10(10):2515. https://doi.org/10.3390/cells10102515

Chicago/Turabian Style

Wang, Chun-I., Yi-Fang Chang, Zong-Lin Sie, Ai-Sheng Ho, Jung-Shan Chang, Cheng-Liang Peng, and Chun-Chia Cheng. 2021. "Irradiation Suppresses IFNγ-Mediated PD-L1 and MCL1 Expression in EGFR-Positive Lung Cancer to Augment CD8+ T Cells Cytotoxicity" Cells 10, no. 10: 2515. https://doi.org/10.3390/cells10102515

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