Regulatory T cells, especially ICOS+ FOXP3+ regulatory T cells, are increased in the hepatocellular carcinoma microenvironment and predict reduced survival

Tu, Jianfei; Ding, Ye; Xiao, Ying; Wu, Fazong; Zhou, Xiao-cong; Zhang, Deng-Ke; Zou, Hai; Ji, Jiansong

doi:10.1038/srep35056

Cited by 117 publications

(107 citation statements)

References 33 publications

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“…While the probability to die from lung cancer before age 75 is for non-smoking females and males 0.2 or 0.4%, this risk increases dose-dependently to 5.5 or 2.6% for former smokers, 15.9 and 9.5% for current smokers and 24.4 and 18.5% for heavy smokers50. Based on the results from our allergy mouse model we anticipated that the acrolein-associated immune suppression could be detrimental in cancer, as it is generally accepted that in many cancer types like breast cancer51, hepatocellular52 and gastric cancer53 an immunosuppressive tumor microenvironment and the extent of intratumoral Foxp3+ expression correlates with disease progression and poor prognosis545556. In our BALB/c mouse tumor model using syngenic D2F2 mammary cancer cells as a model of any type of cancer, acrolein exposure resulted in enhanced tumor growth associated with an accumulation of intratumoral Foxp3+ cells.…”

Section: Discussionmentioning

confidence: 80%

Janus-faced Acrolein prevents allergy but accelerates tumor growth by promoting immunoregulatory Foxp3+ cells: Mouse model for passive respiratory exposure

Roth‐Walter

Bergmayr

Meitz

et al. 2017

Sci Rep

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Acrolein, a highly reactive unsaturated aldehyde, is generated in large amounts during smoking and is best known for its genotoxic capacity. Here, we aimed to assess whether acrolein at concentrations relevant for smokers may also exert immunomodulatory effects that could be relevant in allergy or cancer. In a BALB/c allergy model repeated nasal exposure to acrolein abrogated allergen-specific antibody and cytokine formation, and led to a relative accumulation of regulatory T cells in the lungs. Only the acrolein-treated mice were protected from bronchial hyperreactivity as well as from anaphylactic reactions upon challenge with the specific allergen. Moreover, grafted D2F2 tumor cells grew faster and intratumoral Foxp3+ cell accumulation was observed in these mice compared to sham-treated controls. Results from reporter cell lines suggested that acrolein acts via the aryl-hydrocarbon receptor which could be inhibited by resveratrol and 3′-methoxy-4′-nitroflavone Acrolein- stimulation of human PBMCs increased Foxp3+ expression by T cells which could be antagonized by resveratrol. Our mouse and human data thus revealed that acrolein exerts systemic immunosuppression by promoting Foxp3+ regulatory cells. This provides a novel explanation why smokers have a lower allergy, but higher cancer risk.

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Section: Discussionmentioning

confidence: 80%

Janus-faced Acrolein prevents allergy but accelerates tumor growth by promoting immunoregulatory Foxp3+ cells: Mouse model for passive respiratory exposure

Roth‐Walter

Bergmayr

Meitz

et al. 2017

Sci Rep

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“…We found that the tumor boundary CN was an important site of antitumoral activity, with the frequency of CD4 + T cells and the CD4 + /CD8 + T cell ratio having significant prognostic values in DII patients. Furthermore, DII patients showed increased enrichment of several unexpected cell types in the tumor boundary CN, including activated ICOS + Tregs, which were recently shown to be increased in the hepatocellular carcinoma iTME and predictive of reduced survival (Tu et al, 2016). Interestingly, in DII patients there was direct communication between T cells in CN-6 (tumor boundary) and Tregs in CN-4 (macrophage enriched).…”

Section: Discussionmentioning

confidence: 88%

Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front

Schürch

Bhate

Barlow

et al. 2019

Preprint

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Antitumoral immunity requires organized, spatially nuanced interactions between components of the immune tumor microenvironment (iTME). Understanding this coordinated behavior in effective versus ineffective tumor control will advance immunotherapies. We optimized CO-Detection by indEXing (CODEX) for paraffin-embedded tissue microarrays, enabling profiling of 140 tissue regions from 35 advanced-stage colorectal cancer (CRC) patients with 56 protein markers simultaneously. We identified nine conserved, distinct cellular neighborhoods (CNs)-a collection of components characteristic of the CRC iTME. Enrichment of PD-1 + CD4 + T cells only within a granulocyte CN positively correlated with survival in a high-risk patient subset. Coupling of tumor and immune CNs, fragmentation of T cell and macrophage CNs, and disruption of inter-CN communication was associated with inferioroutcomes. This study provides a framework for interrogating complex biological processes, such as antitumoral immunity, demonstrating an example of how tumors can disrupt immune functionality through interference in the concerted action of cells and spatial domains.

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“…Overall the ICOS/ICOS-LG signalling pathway has been shown to regulate immune cell homeostasis and be implicated in the overall immune response ( 14, 15 ). Of relevance, the accumulation of ICOS + T Reg cells in the TME has been shown to be associated with disease progression in cancer patients ( 16, 17 ). In marked contrast, the upregulation of ICOS on CD4 T EFF cells has been associated with an anti-tumour response and better prognosis in patients after treatment with anti-CTLA-4 ( 18–21 ).…”

Section: Introductionmentioning

confidence: 99%

A novel antibody targeting ICOS increases intratumoural cytotoxic to regulatory T cell ratio and induces tumour regression

Sainson

Thotakura

Kosmač

et al. 2019

Preprint

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25The immunosuppressive tumour microenvironment constitutes a significant hurdle to the 26 response to immune checkpoint inhibitors. Both soluble factors and specialised immune cells 27 such as regulatory T cells (TReg) are key components of active intratumoural 28 immunosuppression. Previous studies have shown that Inducible Co-Stimulatory receptor 29 (ICOS) is highly expressed in the tumour microenvironment, especially on TReg, suggesting that 30 it represents a relevant target for preferential depletion of these cells. Here, we used immune 31 profiling of samples from tumour bearing mice and cancer patients to characterise the 32 expression of ICOS in different tissues and solid tumours. By immunizing an Icos knockout 33 transgenic mouse line expressing antibodies with human variable domains, we selected a fully 34 human IgG1 antibody called KY1044 that binds ICOS from different species. Using KY1044, we 35 demonstrated that we can exploit the differential expression of ICOS on T cell subtypes to 36 modify the tumour microenvironment and thereby improve the anti-tumour immune 37 response. We showed that KY1044 induces sustained depletion of ICOS high TReg cells in mouse 38 tumours and depletion of ICOS high T cells in the blood of non-human primates, but was also 39 associated with secretion of pro-inflammatory cytokines from ICOS low TEFF cells. Altogether, 40 KY1044 improved the intratumoural TEFF:TReg ratio and increased activation of TEFF cells, 41 resulting in monotherapy efficacy or in synergistic combinatorial efficacy when administered 42 with the immune checkpoint blocker anti-PD-L1. In summary, our data demonstrate that 43 targeting ICOS with KY1044 can favourably alter the intratumoural immune contexture, 44 promoting an anti-tumour response. 45 46 48 targeting immune checkpoints (e.g. CTLA-4, PD-1 and PD-L1). These immune checkpoint 49 inhibitors (ICIs) are associated with strong and durable responses in patients suffering from 50 advanced malignancies, including but not limited to metastatic melanoma, non-small cell lung 51 cancer (NSCLC), head and neck cancer, renal and bladder cancer (1). However, within all these 52 indications, there are still a high proportion of patients who exhibit intrinsic or acquired 53 resistance to ICIs. These patients represent a population with high unmet medical needs who 54 may benefit from novel combinatory approaches with ICIs. 55 Multiple molecular and cellular mechanisms have been associated with the lack of response to 56 immunotherapies (2). Accumulating evidence has shown that a low incidence of cytotoxic T 57 cells and the presence of immunosuppressive cells represent major barriers to establishing a 58 response to ICIs. One such class of immunosuppressive cells are regulatory T cells (TReg), which 59 are characterised by the expression of the transcription factor FOXP3 and function by blocking 60 the activation and cytotoxic potential of effector T-cells (TEff) through multiple mechanisms (3, 61 4). In fact, numbers of intratumoural TReg cells neg...

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Regulatory T cells, especially ICOS+ FOXP3+ regulatory T cells, are increased in the hepatocellular carcinoma microenvironment and predict reduced survival

Cited by 117 publications

References 33 publications

Janus-faced Acrolein prevents allergy but accelerates tumor growth by promoting immunoregulatory Foxp3+ cells: Mouse model for passive respiratory exposure

Janus-faced Acrolein prevents allergy but accelerates tumor growth by promoting immunoregulatory Foxp3+ cells: Mouse model for passive respiratory exposure

Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front

A novel antibody targeting ICOS increases intratumoural cytotoxic to regulatory T cell ratio and induces tumour regression

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