Nicotine exhausts CD8+ T cells against tumor cells through increasing miR-629-5p to repress IL2RB-mediated granzyme B expression

Cheng, Chun; Lin, Hong‐Ping; Chiang, Ya Wen; Chang, Jungshan; Sie, Zong-Lin; Yang, Bi Ling; Lim, Ken‐Hong; Peng, Cheng‐Liang; Ho, Ai Sheng; Chang, Yi

doi:10.1007/s00262-020-02770-x

Cited by 13 publications

(17 citation statements)

References 51 publications

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“…We have previously demonstrated that CD16 (FcγRIIIA) and CD122 (IL2/IL15Rβ) are correlated in the healthy CD8 + T cells [11]. This study also evaluated and demonstrated CD16-highly expressed CD8 + T cells possessed higher anti-HCC827 capacity compared to CD16-low expressed CD8 + T cells.…”

Section: Discussionmentioning

confidence: 68%

“…This study also evaluated and demonstrated CD16-highly expressed CD8 + T cells possessed higher anti-HCC827 capacity compared to CD16-low expressed CD8 + T cells. To our knowledge, CD16 on CD8 + T cells acts as an activation site exerting antibody-dependent cellular cytotoxicity (ADCC) function, the levels of which are decreased in exhausted CD8 + T cells treated by nicotine treatment and in smokers [11]. CD16 + CD8 + T cells exhibit natural killer (NK)-like and are terminally differential memory effector T phenotype with high levels of granzyme B and perforin [6,40], indicating this small group of effector CD8 + T cells may exhibit anti-tumor potential since granzyme B and perforin causes tumor apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…The procedure for PBMCs and CD8 + T cell isolation was the same described previously [9]. In brief, blood was collected and analyzed from the individual healthy volunteer (n = 16, Table S1) in Mackay Memorial Hospital, Taipei, Taiwan.…”

Section: Isolation Of Peripheral Blood Mononuclear Cells (Pbmcs) and Cd8 + T Cellsmentioning

confidence: 99%

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Irradiation suppresses STAT3-mediated MCL1 expression to augment CD8+ T cells cytotoxicity against EGFR-positive lung cancer

Wang

Chang

Sie

et al. 2021

Preprint

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Background Tumor cells progress to evade immunological attacks and prohibit activity of CD8+ T cells. Irradiation damages tumor cells and augments tumor immunotherapy in clinical application. However, the detail mechanism remains elusive. We aimed to uncover the mechanism of irradiation augmenting cytotoxic CD8+ T cells to suppress tumor progression in non-small-cell lung cancer (NSCLC). Methods EGFR-positive NSCLC cell lines were co-cultured with isolated PBMCs from healthy volunteers, cell viability and apoptosis were measured. RNAseq was used to screen the IFNγ-mediated gene expression in A549 cells. Irradiation was used to augment PBMCs-mediated anti-tumor effect and the irradiation effect to IFNγ-mediated gene expression was investigated using qPCR and Western blots. Results Co-culture of tumor cells stimulates increase of granzyme B and IFNγ in CD8+ T, but A549 exhibits resistance against CD8+ T cytotoxicity. Irradiation inhibits A549 proliferation and enhances apoptosis, augmenting PBMCs-mediated cytotoxicity against A549. IFNγ simultaneously increased phosphorylation on STAT1 and STAT3 in EGFR-positive lung cancer, resulting in overexpression of PD-L1. In RNAseq analysis, MCL1 was identified and increased by IFNγ-STAT3 axis in A549 cells, we found that irradiation specifically inhibits phosphorylation on STAT1 and STAT3 in IFNr-treated A549, resulting in reductions of PD-L1 and MCL1. Moreover, knockdowns of STAT3 and MCL1 increased PBMCs against irradiated A549 cells. Conclusion This study demonstrated that A549 expressed MCL1 against CD8+ T cell-mediated apoptosis. In addition, we found that irradiation suppressed STAT3 phosphorylation and IFNγ-mediated PD-L1 and MCL1 expression, revealing a potential mechanism of irradiation augmenting immune surveillance.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

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Irradiation suppresses STAT3-mediated MCL1 expression to augment CD8+ T cells cytotoxicity against EGFR-positive lung cancer

Wang

Chang

Sie

et al. 2021

Preprint

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“…There were nine volunteers participated in this study. Individual 20 mL of blood was collected, and the peripheral blood mononuclear cells (PBMCs) were harvested in 4 h with the isolation procedures described previously [37]. The study protocol was approved by regulatory authorities and Institutional Review Boards in Mackay Memorial Hospital (20MMHIS018e).…”

Section: Healthy Volunteersmentioning

confidence: 99%

“…The procedure for PBMCs and CD8 + T cell isolation was the same described previously [37]. In brief, blood samples were collected and analyzed from the individual healthy volunteers (n = 9) in Mackay Memorial Hospital, Taipei, Taiwan.…”

Section: Isolation Of Peripheral Blood Mononuclear Cells (Pbmcs) and Cd8 + T Cellsmentioning

confidence: 99%

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

Wang

Chang

Sie

et al. 2021

Cells

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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.

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CD8+ T-cell exhaustion: Impediment to triple-negative breast cancer (TNBC) immunotherapy

Feng,

Pu,

Ren

et al. 2024

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Nicotine exhausts CD8+ T cells against tumor cells through increasing miR-629-5p to repress IL2RB-mediated granzyme B expression

Cited by 13 publications

References 51 publications

Irradiation suppresses STAT3-mediated MCL1 expression to augment CD8+ T cells cytotoxicity against EGFR-positive lung cancer

Irradiation suppresses STAT3-mediated MCL1 expression to augment CD8+ T cells cytotoxicity against EGFR-positive lung cancer

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

CD8+ T-cell exhaustion: Impediment to triple-negative breast cancer (TNBC) immunotherapy

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