Ilse Mollet

Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells

Squamous cell carcinomas (SCCs) of the skin are sun-induced skin cancers that are particularly numerous in patients on T cell immunosuppression. We found that blood vessels in SCCs did not express E-selectin, and tumors contained few cutaneous lymphocyte antigen (CLA)+ T cells, the cell type thought to provide cutaneous immunosurveillance. Tumors treated with the Toll-like receptor (TLR)7 agonist imiquimod before excision showed induction of E-selectin on tumor vessels, recruitment of CLA+ CD8+ T cells, and histological evidence of tumor regression. SCCs treated in vitro with imiquimod also expressed vascular E-selectin. Approximately 50% of the T cells infiltrating untreated SCCs were FOXP3+ regulatory T (T reg) cells. Imiquimod-treated tumors contained a decreased percentage of T reg cells, and these cells produced less FOXP3, interleukin (IL)-10, and transforming growth factor (TGF)-β. Treatment of T reg cells in vitro with imiquimod inhibited their suppressive activity and reduced FOXP3, CD39, CD73, IL-10, and TGF-β by indirect mechanisms. In vivo and in vitro treatment with imiquimod also induced IL-6 production by effector T cells. In summary, we find that SCCs evade the immune response at least in part by down-regulating vascular E-selectin and recruiting T reg cells. TLR7 agonists neutralized both of these strategies, supporting their use in SCCs and other tumors with similar immune defects.

Imiquimod Enhances IFN-γ Production and Effector Function of T Cells Infiltrating Human Squamous Cell Carcinomas of the Skin

Squamous cell carcinomas (SCCs) are sun-induced skin cancers that are particularly numerous and aggressive in patients taking T-cell immunosuppressant medications. Imiquimod is a topical immune response modifier and Toll-like receptor 7 (TLR7) agonist that induces the immunological destruction of SCC and other skin cancers. TLR7 activation by imiquimod has pleiotropic effects on innate immune cells, but its effects on T cells remain largely uncharacterized. Because tumor destruction and formation of immunological memory are ultimately T-cell-mediated effects, we studied the effects of imiquimod therapy on effector T cells infiltrating human SCC. SCC treated with imiquimod before excision contained dense T-cell infiltrates associated with tumor cell apoptosis and histological evidence of tumor regression. Effector T cells from treated SCC produced more IFN-gamma, granzyme, and perforin and less IL-10 and transforming growth factor-beta (TGF-beta) than T cells from untreated tumors. Treatment of normal human skin with imiquimod induced activation of resident T cells and reduced IL-10 production but had no effect on IFN-gamma, perforin, or granzyme, suggesting that these latter effects arise from the recruitment of distinct populations of T cells into tumors. Thus, imiquimod stimulates tumor destruction by recruiting cutaneous effector T cells from blood and by inhibiting tonic anti-inflammatory signals within the tumor.

New insights in segmental vitiligo: case report and review of theories

Segmental vitiligo and generalized vitiligo are in general considered to be separate entities. The aetiopathogenesis of segmental vitiligo remains unclear, although several hypotheses have been put forward including mainly neuronal mechanisms. The typical association with other autoimmune diseases, as seen in generalized vitiligo, seems to be significantly less in segmental vitiligo, although recent insights point towards a possible immune‐mediated overlap between the two subtypes. In this article, we describe a case with simultaneous presence of segmental vitiligo, alopecia areata, psoriasis and a halo naevus. To our knowledge, this is the first case with this exceptional combination. This concomitant presence could support the involvement of a shared autoimmune‐mediated process, and may provide new insights into the pathogenesis of segmental vitiligo and direct future research. In the light of this remarkable case, different possible aetiopathogenetic mechanisms leading to the clinical presentation of segmental vitiligo are discussed and a new three‐step theory is proposed.

In vivo vitiligo induction and therapy model: double-blind, randomized clinical trial.

In this study, we developed an in vivo vitiligo induction model to explore the underlying mechanisms leading to Koebner’s phenomenon and to evaluate the efficacy of therapeutic strategies. The model consisted of 12 pigmented test regions on the back of generalized vitiligo patients that were exposed to three Koebner induction methods: cryotherapy, 755 nm laser therapy, and epidermal abrasion. In addition, four cream treatments (pimecrolimus, tacrolimus, steroid and placebo) were randomly applied. Koebnerization was efficiently induced by all three induction methods. In general, cryotherapy was the best method of Koebner induction, followed by 755 nm laser therapy and epidermal abrasion. Reproducible results were obtained, which showed enhanced depigmented surface areas and higher amounts of T lymphocytes in placebo‐treated test zones compared to active treated areas. Tacrolimus and local steroids were better inhibitors of Koebner’s process (P < 0.05) compared to pimecrolimus. Our in vivo vitiligo induction model is very informative to investigate vitiligo induction and to determine the efficacy of topical treatments in vitiligo. This proof of concept confirms the efficient comparison of head‐to‐head therapeutic strategies intra‐individually in a standardized, specific and better timed way.

Different phenotypes of segmental vitiligo based on a clinical observational study.

Background  Segmental vitiligo and generalized vitiligo are in general considered separate entities. However, clinico‐epidemiological data on segmental vitiligo are scarce compared with those of generalized vitiligo.

Prognostic value and clinical significance of halo naevi regarding vitiligo

Background  Vitiligo and halo naevi can present together or separately. Whether they are different entities remains unclear.

Halo naevi with associated vitiligo-like depigmentations: pathogenetic hypothesis.

Background  In analogy with melanoma‐associated leucoderma, halo naevi may trigger in some patients the development of additional depigmentations which are in distribution, extent and prognosis not in accordance with classic vitiligo.

Autoimmune/Inflammatory and Other Diseases Associated with Vitiligo

Although the exact aetiology of vitiligo remains unclear, vitiligo is widely considered to have an autoimmune component in its pathogenesis based on disease associations. According to ethnic background, large variations exist in association with autoinflamma-tory/autoimmune disorders. Some reported associations may reflect a simple coexistence of two disorders, and the repertoire of associations may help to detect shared heritable predispositions for inflamma-tion and autoimmunity. Thyroid disorders are the most commonly associated to vitiligo in Caucasian populations, alopecia areata in Chinese populations, rheumatoid arthritis (RA) being more rarely associated in both.