Loss of Cutaneous TSLP-Dependent Immune Responses Skews the Balance of Inflammation from Tumor Protective to Tumor Promoting

Piazza, Matteo; Nowell, Craig S.; Koch, Ute; Durham, André-Dante; Radtke, Freddy

doi:10.1016/j.ccr.2012.08.016

Cited by 109 publications

(102 citation statements)

References 47 publications

(64 reference statements)

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“…The overall role of CD4 T cells in the incidence of preneoplastic lesions and SCCs in the skin has also been supported by other studies using the K14-HPV tumor-prone mice (Kemp et al 1999;Daniel et al 2003;de Visser et al 2005). Unlike CD4 T cells, CD8 T cells seem to protect against skin carcinogenesis (Di Piazza et al 2012), in agreement with the current view in cancer and inflammation assigning a protective effect to cytotoxic CD8 T cells and a tumor-promoting effect to helper CD4 T cells (Shiao et al 2011;Brown et al 2012). Nevertheless, there are some specific cases where CD4 T cells may have a tumor-protective role (Demehri et al 2012).…”

Section: Discussionsupporting

confidence: 61%

Inflammation-mediated skin tumorigenesis induced by epidermal c-Fos

et al. 2013

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Skin squamous cell carcinomas (SCCs) are the second most prevalent skin cancers. Chronic skin inflammation has been associated with the development of SCCs, but the contribution of skin inflammation to SCC development remains largely unknown. In this study, we demonstrate that inducible expression of c-fos in the epidermis of adult mice is sufficient to promote inflammation-mediated epidermal hyperplasia, leading to the development of preneoplastic lesions. Interestingly, c-Fos transcriptionally controls mmp10 and s100a7a15 expression in keratinocytes, subsequently leading to CD4 T-cell recruitment to the skin, thereby promoting epidermal hyperplasia that is likely induced by CD4 T-cell-derived IL-22. Combining inducible c-fos expression in the epidermis with a single dose of the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) leads to the development of highly invasive SCCs, which are prevented by using the anti-inflammatory drug sulindac. Moreover, human SCCs display a correlation between c-FOS expression and elevated levels of MMP10 and S100A15 proteins as well as CD4 T-cell infiltration. Our studies demonstrate a bidirectional cross-talk between premalignant keratinocytes and infiltrating CD4 T cells in SCC development. Therefore, targeting inflammation along with the newly identified targets, such as MMP10 and S100A15, represents promising therapeutic strategies to treat SCCs.

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Section: Discussionsupporting

confidence: 61%

Inflammation-mediated skin tumorigenesis induced by epidermal c-Fos

et al. 2013

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“…59 Moreover, cutaneous infiltration of chronic lymphocytic leukemia predisposes to SCC development, 60 although CD4 + and CD8 + T cells can also confer protection against SCC in Notch-deficient mice. 61 Remarkably, even though adaptive immunity is markedly attenuated in old age, we observe massive recruitment of lymphocytes to the old skin following H-Ras activation. The immune response in the old skin is skewed toward a Th2-suppressive mode, including elevated levels of IL10 and IL4 and accumulation of mast cells.…”

Section: Discussionmentioning

confidence: 91%

Age-associated inflammation connects RAS-induced senescence to stem cell dysfunction and epidermal malignancy

et al. 2015

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Aging is the single biggest risk factor for malignant transformation. Among the most common age-associated malignancies are non-melanoma skin cancers, comprising the most common types of human cancer. Here we show that mutant H-Ras activation in mouse epidermis, a frequent event in cutaneous squamous cell carcinoma (SCC), elicits a differential outcome in aged versus young mice. Whereas H-Ras activation in the young skin results in hyperplasia that is mainly accompanied by rapid hair growth, H-Ras activation in the aged skin results in more dysplasia and gradual progression to in situ SCC. Progression is associated with increased inflammation, pronounced accumulation of immune cells including T cells, macrophages and mast cells as well as excessive cell senescence. We found not only an age-dependent increase in expression of several pro-inflammatory mediators, but also activation of a strong anti-inflammatory response involving enhanced IL4/IL10 expression and immune skewing toward a Th2 response. In addition, we observed an age-dependent increase in the expression of Pdl1, encoding an immune suppressive ligand that promotes cancer immune evasion. Moreover, upon switching off oncogenic H-Ras activity, young but not aged skin regenerates successfully, suggesting a failure of the aged epidermal stem cells to repair damaged tissue. Our findings support an age-dependent link between accumulation of senescent cells, immune infiltration and cancer progression, which may contribute to the increased cancer risk associated with old age.

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“…49 Loss of Notch in the epidermis is strongly linked with the induction of systemic immune changes and stromal inflammation. 48,69,70 Interestingly there is no evidence of epithelial, stromal or systemic immune changes following DNMaml1 expression in the esophagus, likely reflecting organ specific tuning of the immune system. These observations suggest a cellular mechanism for the phenomenon of 'field change', observed in carcinogen exposed human epithelia.…”

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confidence: 99%