Bacterial infections and cancer

Elsland, Daphne M. van; Neefjes, Jacques

doi:10.15252/embr.201846632

Cited by 158 publications

(125 citation statements)

References 107 publications

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“…upregulates proinflammatory cytokines, chemokines, and cell adhesion molecules in keratinocytic cells, both primary cultures and SCC lines, through activation of the canonical NF‐κB pathway. In keeping with other bacterial pathogens, we confirmed the inflammatory role played by IKK . Using fluorescent microscopy and Western blot analysis, we demonstrated that phosphorylation of IκB is C. t .‐dependent.…”

Section: Discussionsupporting

confidence: 83%

“…In keeping with other bacterial pathogens, we confirmed the inflammatory role played by IKK. [65][66][67][68][69] Using fluorescent microscopy and Western blot analysis, we demonstrated that phosphorylation of IκB is C. t.-dependent. Furthermore, the inhibition of IKK by the specific inhibitor PS-1145 70 significantly reduced the mRNA and protein expression of proinflammatory molecules induced by C. t., indicating these effects are mediated, at least in major part, by IKK.…”

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confidence: 95%

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Corynebacterium tuberculostearicum, a human skin colonizer, induces the canonical nuclear factor‐κB inflammatory signaling pathway in human skin cells

Altonsy

Kurwa

Lauzon

et al. 2020

Immunity Inflam & Disease

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Introduction Corynebacterium tuberculostearicum (C. t.) is a ubiquitous bacterium that colonizes human skin. In contrast to other members of the genus Corynebacterium, such as toxigenic Corynebacterium diphtheriae or the opportunistic pathogen Corynebacterium jeikeium, several studies suggest that C. t. may play a role in skin health and disease. However, the mechanisms underlying these effects remain poorly understood. Methods To investigate whether C. t. induces inflammatory pathways in primary human epidermal keratinocytes (HEKs) and human cutaneous squamous carcinoma cells (SCCs), cell culture, reverse transcription‐polymerase chain reaction (PCR), enzyme‐linked immunosorbent assay, immunofluorescence microscopy, Western blot, chromatin immunoprecipitation‐PCR, small interfering RNA knockdown and luciferase reporter expression system were used. Results Herein, we demonstrate that C. t. upregulates the messenger RNA (mRNA) and protein levels of inflammatory mediators in two human skin cell lines, HEKs and SCCs. We further show activation of the canonical nuclear factor‐κB (NF‐κB) pathway in response to C. t. infection, including phosphorylation of the inhibitor of κB (IκB), the nuclear translocation of NF‐κB subunit (NF‐κB‐P65) and the recruitment of NF‐κB‐P65 and RNA polymerase to the NF‐κB response elements at the promoter region of the inflammatory genes. Lastly, the data confirm that C. t.‐induced tumor necrosis factor mRNA expression in HEKs is toll‐like receptor 2 (TLR2) dependent. Conclusion Our results offer a mechanistic model for C. t.‐induced inflammation in human keratinocytes via TLR2 and activation of IκB kinase and downstream signaling through the canonical NF‐κB pathway. Relevance to chronic inflammatory diseases of the skin and cutaneous oncology is discussed.

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Section: Discussionsupporting

confidence: 83%

mentioning

confidence: 95%

Corynebacterium tuberculostearicum, a human skin colonizer, induces the canonical nuclear factor‐κB inflammatory signaling pathway in human skin cells

Altonsy

Kurwa

Lauzon

et al. 2020

Immunity Inflam & Disease

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“…This further suggests that bacterial rather than viral infection status should be considered in the development of targeted therapies in VSCC. Prevention and control of bacterial infections are anticipated to become a valuable addition to current cancer treatment modalities [63]. Finally, several lines of evidence for similarities in the biology of ANCA-associated vasculitis provides grounds for the assumption that VSCC patients might bene t from treatments currently applied in AVV and other neutrophilic human diseases such as COPD.…”

Section: Discussionmentioning

confidence: 99%

Inflammation as a Driver of Vulvar Squamous Cell Carcinoma Progression.

Fatalska¹,

Rusetska²,

Bakuła-Zalewska³

et al. 2020

Preprint

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Background A knowledge on the biology of squamous cell vulvar carcinoma (VSCC) is limited. We aimed to identify protein markers of VSCC tumors stratifying patients by progression risk. Early stage VSCC tumors from patients who progressed (progVSCC) and from those who were disease-free (d-fVSCC) during follow-up, along with normal vulvar tissues were examined by mass spectrometry-based proteomics.Results In progVSCC vs d-fVSCC tumors, the immune response was the most over-represented Gene Ontology category for the identified DEPs. Interestingly, pathway profiling suggested bacterial infections to be linked to aggressive VSCC phenotypes. Differentially expressed proteins (DEPs) were verified in solid tissues and blood samples of patients with VSCC tumors and vulvar premalignant lesions. High Mobility Group AT-Hook 2 (HMGA2) and Proteinase 3 (PRTN3) were revealed as protein markers predicting VSCC progression.Conclusions HMGA2 and PRTN3 abundances are associated with aggressive VSCC phenotype, and hold promise as markers for patient stratification. It appears that vulvovaginal microflora disturbances trigger inflammatory response contributing to cancer progression.

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“…In addition, ICOS induction on T Reg has been reported in chronic infectious disease ( 43 ). This is also relevant since several of the above preferred tumours that have high levels of ICOS + T Reg are also often associated with chronic viral or bacterial infections ( 44 ). At this stage, it is not yet clear if these T Reg are pathogen-specific and are inhibiting the anti-tumour immune response as a “bystander effect”.…”

Section: Discussionmentioning

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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Bacterial infections and cancer

Cited by 158 publications

References 107 publications

Corynebacterium tuberculostearicum, a human skin colonizer, induces the canonical nuclear factor‐κB inflammatory signaling pathway in human skin cells

Corynebacterium tuberculostearicum, a human skin colonizer, induces the canonical nuclear factor‐κB inflammatory signaling pathway in human skin cells

Inflammation as a Driver of Vulvar Squamous Cell Carcinoma Progression.

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

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