IL-2 regulates tumor-reactive CD8+ T cell exhaustion by activating the aryl hydrocarbon receptor

Liu, Yuying; Zhou, Nannan; Zhou, Li; Wang, Jing; Zhou, Yabo; Zhang, Tianzhen; Fang, Yi; Deng, Jinwei; Gao, Yunfeng; Liang, Xiaoyu; Lv, Jiadi; Wang, Zhenfeng; Xie, Jing; Xue, Yuanbo; Zhang, Huafeng; Ma, Jingwei; Tang, Ke; Fang, Yiliang; Cheng, Feiran; Zhang, Chengjuan; Dong, Bing; Zhao, Yuzhou; Yuan, Peng; Gao, Quanli; Zhang, Haizeng; Qin, F. Xiao-Feng; Huang, Bo

doi:10.1038/s41590-020-00850-9

Cited by 193 publications

(160 citation statements)

References 51 publications

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“…Aim to figure out the specific shifts of immune status in the malignant transformation, we then calculated the exhausted T cell score with average expression values within the genes in signature 27 and performed the overrepresentation analysis of the DEGs in the immune signatures collection as well. We noticed exhausted T cell score started rocketing from HSIL and reached the peak in SCC ( Figure 3G), which also supported the former conclusion that immune escape occurred before malignancy.…”

Section: Changes Of Local Immune Cells and Immune-modulatory Genes mentioning

confidence: 99%

The immune landscape during the tumorigenesis of cervical cancer

Wang

Zhang

et al. 2021

Cancer Medicine

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Section: Changes Of Local Immune Cells and Immune-modulatory Genes mentioning

confidence: 99%

The immune landscape during the tumorigenesis of cervical cancer

Wang

Zhang

et al. 2021

Cancer Medicine

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“…Mechanistically, BaP can directly activate aryl hydrocarbon receptor (AhR), induce IL-33 expression and eosinophil infiltration in a mouse model of allergic airway inflammation (17), and elicit T-helper 2-driven pro-inflammatory responses in a mouse model of allergic dermatitis (18). AhR, as a ligandactivated transcription factor, can be activated by small molecules in various diets, metabolites, microorganisms, and pollutants (19)(20)(21)(22)(23)(24) and plays an important role in the regulation of innate and adaptive immune responses (25)(26)(27)(28). Of note is that we have recently made a novel finding that BaP co-exposure with dermatophagoides farina group 1 allergen (Der f 1) can potentiate Der f 1-induced airway hyper-responsiveness (AHR) and lung inflammation (29).…”

Section: Introductionmentioning

confidence: 99%

Benzo(a)pyrene Enhanced Dermatophagoides Group 1 (Der f 1)-Induced TGFβ1 Signaling Activation Through the Aryl Hydrocarbon Receptor–RhoA Axis in Asthma

Wang

Danh

et al. 2021

Front. Immunol.

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We have previously demonstrated that benzo(a)pyrene (BaP) co-exposure with dermatophagoides group 1 allergen (Der f 1) can potentiate Der f 1-induced airway inflammation. The underlying mechanism, however, remains undetermined. Here we investigated the molecular mechanisms underlying the potentiation of BaP exposure on Der f 1-induced airway inflammation in asthma. We found that BaP co-exposure potentiated Der f 1-induced TGFβ1 secretion and signaling activation in human bronchial epithelial cells (HBECs) and the airways of asthma mouse model. Moreover, BaP exposure alone or co-exposure with Der f 1-induced aryl hydrocarbon receptor (AhR) activity was determined by using an AhR-dioxin-responsive element reporter plasmid. The BaP and Der f 1 co-exposure-induced TGFβ1 expression and signaling activation were attenuated by either AhR antagonist CH223191 or AhR knockdown in HBECs. Furthermore, AhR knockdown led to the reduction of BaP and Der f 1 co-exposure-induced active RhoA. Inhibition of RhoA signaling with fasudil, a RhoA/ROCK inhibitor, suppressed BaP and Der f 1 co-exposure-induced TGFβ1 expression and signaling activation. This was further confirmed in HBECs expressing constitutively active RhoA (RhoA-L63) or dominant-negative RhoA (RhoA-N19). Luciferase reporter assays showed prominently increased promoter activities for the AhR binding sites in the promoter region of RhoA. Inhibition of RhoA suppressed BaP and Der f 1 co-exposure-induced airway hyper-responsiveness, Th2-associated airway inflammation, and TGFβ1 signaling activation in asthma. Our studies reveal a previously unidentified functional axis of AhR–RhoA in regulating TGFβ1 expression and signaling activation, representing a potential therapeutic target for allergic asthma.

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“…Specifically, it was reported that persistently high levels of IL-2 production in TME lead to the long-lasting activation of signal transducer and activator of transcription 5, STAT5, in CD8 + T cells, which in turn induced strong expression of tryptophan hydroxylase 1 (5-HTP), thus catalyzing the conversion of Trp into 5-hydroxytryptophan. AhR activated by 5-HTP directly induced tumor-specific CD8 + TILs cell exhaustion in vivo, causing a coordinated upregulation of inhibitory receptors, such as PD-1, LAG-3, CD39 and downregulation of cytokines, thereby causing dysfunctional T cells in the TME [ 61 ]. This study clearly highlights that IL-2, by virtue of activation of a novel STAT5–5-HTP–AhR axis, induced CD8 + T cell exhaustion in the TME.…”

Section: The Various Trp Metabolic Pathways and Metabolites In The Regulation Of Immune Responses To Tumor Cells Via Ahr Activationmentioning

confidence: 99%

Tryptophan Metabolites at the Crossroad of Immune-Cell Interaction via the Aryl Hydrocarbon Receptor: Implications for Tumor Immunotherapy

Gargaro

Manni

Scalisi

et al. 2021

IJMS

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The Aryl hydrocarbon receptor (AhR) is a critical regulator of both innate and adaptive immune responses, with potent immunomodulatory effects that makes this receptor an attractive molecular target for novel therapeutics. Accumulating evidence indicates that diverse—both host’s and microbial—tryptophan metabolites profoundly regulate the immune system in the host via AhR, promoting either tolerance or immunity, largely as a function of the qualitative and quantitative nature of the metabolites being contributed by either source. Additional findings indicate that host and microbiota-derived tryptophan metabolic pathways can influence the outcome of immune responses to tumors. Here, we review recent studies on the role and modalities of AhR activation by various ligands, derived from either host-cell or microbial-cell tryptophan metabolic pathways, in the regulation of immune responses. Moreover, we highlight potential implications of those ligands and pathways in tumor immunotherapy, with particular relevance to checkpoint-blockade immune intervention strategies.

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IL-2 regulates tumor-reactive CD8+ T cell exhaustion by activating the aryl hydrocarbon receptor

Cited by 193 publications

References 51 publications

The immune landscape during the tumorigenesis of cervical cancer

The immune landscape during the tumorigenesis of cervical cancer

Benzo(a)pyrene Enhanced Dermatophagoides Group 1 (Der f 1)-Induced TGFβ1 Signaling Activation Through the Aryl Hydrocarbon Receptor–RhoA Axis in Asthma

Tryptophan Metabolites at the Crossroad of Immune-Cell Interaction via the Aryl Hydrocarbon Receptor: Implications for Tumor Immunotherapy

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