Faculty Bibliography

Basal cell carcinoma (BCC), the most common human cancer, undergoes spontaneous regression in certain circumstances, which is potentially immune-mediated. To understand the immune response surrounding BCCs, we characterized the genomic, protein, and cellular microenvironment associated with BCC in comparison to normal skin. Our results demonstrated the following: (1) CD4+ CD25+ Foxp3+ surround epithelial tumor aggregates; (2) Immature dendritic cells (DCs) were abundant in the tumor microenvironment; (3) BCC showed increased expression of IL-4, IL-10, and CCL22 and increased expression of interferon-associated genes (IFI27, IRF1, IRF7, and G1P2) and IL-12/23, gene indicating a Th2 dominant microenvironment. Our findings suggest a dynamic state within the immune microenvironment associated with BCC. The finding of phenotypic T regs, in conjunction with immature DCs and Th2 cytokines, suggests an attenuated state of immunity to human BCC. In contrast, abundant CD8+ T cells, an interferon signal, and IL-12/23 suggest partial host antitumor response. A better understanding of these opposing forces within the immune microenvironment may facilitate development of more potent immune-based treatment for BCC and other human carcinomas

BACKGROUND: Since its inception in 1985, the American Academy of Dermatology (AAD) National Melanoma/Skin Cancer Screening Program has strived to enhance early detection of cutaneous malignant melanoma (MM) by providing nationwide skin cancer education campaigns in combination with free skin cancer screenings. OBJECTIVE: To analyze the AAD screening data from 2001 to 2005 in order to identify factors associated with MM detection, and thereby derive a model of increased likelihood for MM detection through visual skin examinations at screenings. MATERIALS AND METHODS: Patients completed a standardized AAD pre-screening form with historical and phenotypic information. Clinicians then recorded suspected clinical findings noted at visual skin examination. Statistical analyses were conducted using SPSS 14 (SPSS Inc., Chicago, Ill). RESULTS: Five factors, which can be remembered with the acronym HARMM, independently increased the likelihood of suspected MM being found in the 362,804 persons screened: History of previous melanoma (odds ratio [OR] = 3.3; 95% confidence interval [CI], 2.9-3.8); Age over 50 (OR = 1.2; 95% CI, 1.1-1.3); Regular dermatologist absent (OR = 1.4; 95% CI, 1.3-1.5); Mole changing (OR = 2.0; 95% CI, 1.9-2.2); and Male gender (OR = 1.4; 95% CI, 1.3-1.5). Individuals at highest risk (4 or 5 factors) comprised only 5.8% of the total population, yet accounted for 13.6% of presumptive MM findings, and were 4.4 times (95% CI, 3.8-5.1) more likely to be diagnosed with suspected MM than individuals at lowest risk (0 or 1 factor). Receipt of a total skin examination at screening independently increased the likelihood for identifying suspected MM (OR = 1.4; 95% CI, 1.3-1.6). However, significantly fewer screenees in the highest risk group versus those in the lowest risk group underwent total skin examinations (53.7% vs 62.5%). LIMITATIONS: Risk factors studied limited to variables collected in screenee enrollment form. CONCLUSIONS: A higher-risk subgroup of the skin cancer screening population can be identified through assessment of MM risk factors using the HARMM criteria. Refocusing efforts to provide a total skin examination to those individuals with multiple risk factors has the potential to both reduce costs and increase yields for suspected MM in future mass screening initiatives

BACKGROUND: Atopic dermatitis (AD) and psoriasis represent contrasting poles of the T(H)1 versus T(H)2 paradigm. Both diseases have been associated with increased numbers of dendritic cells (DCs) in the skin, but the similarities and differences in DC populations need to be established. OBJECTIVE: We aimed to characterize the specific DC subsets, as well as chemokine and cytokine environment in chronic AD compared with psoriasis. METHODS: Skin biopsies were obtained from patients with acute exacerbation of chronic AD (n = 18), psoriasis (n = 15), and healthy volunteers (n = 15) for microarray analysis, RT-PCR, immunohistochemistry, and double-label immunofluorescence. RESULTS: Myeloid DCs upregulate CCL17 and CCL18 in AD, as opposed to TNF-alpha and inducible nitric oxide synthase (iNOS) in psoriasis. In our study, we identified cells phenotypically identical to the inflammatory dendritic epidermal cells in the dermis in both diseases, although to a lesser extent in psoriasis. We found substantially higher numbers of dermal CCL22 producing plasmacytoid DCs in AD. The thymic stromal lymphopoietin receptor showed significantly higher expression in AD, whereas the thymic stromal lymphopoietin ligand was upregulated more in psoriasis. CONCLUSION: There are major differences in myeloid and plasmacytoid subsets of cutaneous DCs and the chemokine/cytokine environment between AD and psoriasis. Distinct subsets within the CD11c(+) population may influence polarization through the production of regulatory mediators, including iNOS, TNF, CCL17, and CCL18. Plasmacytoid DCs may also influence T(H)2 polarization, having a more important role in AD than previously appreciated. CLINICAL IMPLICATIONS: Dermal inflammatory dendritic cells in AD and TNF and iNOS-producing DCs in psoriasis, and/or their regulatory products, may be potential targets for future therapeutic interventions

Using high-density oligonucleotide arrays, we measured expression of >12,000 genes in surgical excisions of invasive human squamous cell carcinomas (SCCs) versus site-matched control skin. This analysis defined >1,900 genes with altered expression in SCCs that were statistically different from controls. As SCCs are composed of epithelial cells, which are both hyperplastic and invasive, we sought to define gene sets associated with these biologic processes by comparing gene expression to psoriasis vulgaris, which is a condition of benign keratinocyte hyperplasia without invasiveness or pre-malignant potential. Through this analysis, we found genes that were commonly upregulated in both conditions and unique genes with increased expression in SCCs. Differential gene regulation in these two conditions was confirmed by real-time reverse transcription-PCR and immunohistochemistry. We found that benign hyperplasia is associated with upregulation of genes including DEFB4 (defensin B4), SERPINB3 (serine proteinase inhibitor, member 3), STAT1 (signal transducer and activator of transcription 1), K16 (keratin 16), CEACAMs (carcinoembryonic antigen-related cell adhesion molecules), and WNT 5A (wingless-type MMTV integration site family, member 5A). WNT receptor frizzled homolog 6 (FZD6) and prostaglandin-metabolizing enzyme hydroxyprostaglandin dehydrogenase were increased in SCC alone. Growth factor pleiotrophin (PTN) was expressed at higher levels in non-tumor-bearing skin adjacent to excised SCC. SCC was further characterized by upregulation of matrix metalloproteinases 1, 10, and 13, cathepsin L2, cystatin E/M as well as STAT3 and microseminoprotein, beta (MSMB), and downregulation of inducible nitric oxide synthase, granzyme B, CD8, and CD83. The current study defines a unique gene expression signature for cutaneous SCC in humans and suggests potential roles for WNT, FZD, and PTN in the pathogenesis of SCC