Abstract
Basal cell carcinomas (BCC) and squamous-cell carcinomas (SCC) are common malignancies in humans, caused by neoplastic transformation of keratinocytes of the basal or suprabasal layers of epidermis, respectively. Tumor-infiltrating lymphocytes (TILs) are frequently found in BCC and SCC, and functionally promote epithelial carcinogenesis. TILs secreting IL-22, in particular, participate to BCC and SCC growth by inducing keratinocyte proliferation and migration, as well as the expression of inflammatory, anti-apoptotic and pro-angiogenic genes.In this study, we identified SOCS3 as a valid candidate to be manipulated for suppressing tumorigenic functions in BCC and SCC. We found that SOCS3 and SOCS1 expression was reduced in vivo, in tumor lesions of BCC and SCC, as compared to other skin inflammatory conditions such as psoriasis, despite the high number of IL-22-secreting TILs. Moreover, IL-22 was not able to induce in vitro the transcriptional expression of SOCS3 in BCC-or SCC-derived keratinocytes, contrarily to healthy cells. Aimed at rescuing SOCS3 activity in these tumor contexts, a SOCS3-derived peptide, named KIR-ESS, was synthesized, and its ability in suppressing IL-22-induced responses was evaluated in healthy and transformed keratinocytes. We found that KIR-ESS peptide efficiently suppressed the IL-22 molecular signaling in keratinocytes, by acting on STAT3 and Erk1/2 cascade, as well as on the expression of STAT3-dependent downstream genes. Interestingly, after treatment with peptide, both healthy and transformed keratinocytes could no longer aberrantly proliferate and migrate in response to IL-22. Finally, treatment of athymic nude mice bearing SCC xenografts with KIR-ESS peptide concomitantly reduced tumor growth and activated STAT3 levels. As a whole, these data provides the rationale for the use in BCC and SCC skin tumors of SOCS3 mimetics, being able to inhibit the deleterious effects of IL-22 in these contexts.
Highlights
IL-22 belongs to a family of cytokines structurally related to IL-10, and it is secreted exclusively by immune cells, especially type-22 and type-17 T lymphocytes [1, 2]
We found that SOCS3 and SOCS1 expression was reduced in vivo, in tumor lesions of Basal cell carcinomas (BCC) and squamous-cell carcinomas (SCC), as compared to other skin inflammatory conditions such as psoriasis, despite the high number of IL-22-secreting Tumor-infiltrating lymphocytes (TILs)
We firstly demonstrated that in human keratinocytes IL-22 induced molecular cascade implicating phosphorylation of IL-22R1, Tyk2 and Jak1 (Figure 1A), but not of Jak2 that culminated with STAT3, MEK1/2 and Erk1/2 activation (Figure 1B)
Summary
IL-22 belongs to a family of cytokines structurally related to IL-10, and it is secreted exclusively by immune cells, especially type-22 and type-17 T lymphocytes [1, 2]. IL-22 signalling impacts on non-melanoma skin carcinomas (NMSC), including squamous cell carcinomas (SCC) and basal cell carcinomas (BCC) [10, 11]. In these tumour contexts, IL-22, locally released together with IL-17 by tumor-infiltrating lymphocytes (TILs), promotes epithelial carcinogenesis, since it activates proliferation and migration of transformed keratinocytes, as well as the expression of inflammatory and anti-apoptotic molecules which contribute to tumor progression [10, 12]. IL-22-dependent effects in BCC- or SCCderived keratinocytes are mainly mediated by STAT3, by extracellular signal-regulated kinases (Erk)1/2 and the anti-apoptotic Akt pathways [10]
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