Faculty Bibliography

We developed an automated approach for generating quantitative image analysis metrics (imaging biomarkers) that are then analysed with a set of 13 machine learning algorithms to generate an overall risk score that is called a Q-score. These methods were applied to a set of 120 "difficult" dermoscopy images of dysplastic nevi and melanomas that were subsequently excised/classified. This approach yielded 98% sensitivity and 36% specificity for melanoma detection, approaching sensitivity/specificity of expert lesion evaluation. Importantly, we found strong spectral dependence of many imaging biomarkers in blue or red colour channels, suggesting the need to optimize spectral evaluation of pigmented lesions.

Importance: Limited therapies are available in patients with inoperable locally advanced cutaneous squamous cell carcinoma (cSCC). Objective: To determine the efficacy of programmed cell death 1 receptor (PD-1) inhibitors in locally advanced cSCC. Design, Setting, and Participants: A single patient with locally advanced cSCC who declined surgery and radiotherapy underwent treatment with pembrolizumab, an anti-PD-1 antibody, at an academic dermatologic surgery section and cancer center. The patient was followed up for clinical and radiologic regression of cSCC. With the use of NanoString to amplify potential biomarkers, immunohistochemistry, and immunofluorescence, the ex vivo expression of PD-1 and a ligand (PD-L2) was assessed in 38 cSCC biopsy specimens from 24 patients with cSCC. Expression of PD-L1 and PD-L2 in the cSCC microenvironment was defined. Intervention: Pembrolizumab, 2 mg/kg every 3 weeks, for 4 cycles. Main Outcomes and Measures: Expression of PD-L1 and PD-L2 in the cSCC microenvironment. Results: In 1 patient with locally advanced cSCC who was treated with pembrolizumab, nearly complete tumor regression was observed after 4 cycles of therapy. The NanoString technology used in 38 cSCC biopsy specimens from 24 patients with cSCC (19 men and 5 women; mean [SD] age, 76.4 [12.2] years) detected increased PD-1 and PD-L2 expression in high-risk cSCC. Immunohistochemical analysis confirmed enhanced expression of PD-1 and its ligands in cSCC with perineural invasion (mean [SEM] expression, 5.06 [1.27]; P = .05), superficial cSCC (mean [SEM] expression, 3.58 [1.50]; P = .15), organ transplant-associated cSCC (mean [SEM] expression, 3.01 [0.54]; P = .005), and infiltrative cSCC (mean [SD] expression, 2.01 [0.30]; P = .006) compared with normal skin specimens. In double-label immunofluorescence staining, CD11c+, a marker of myeloid dendritic cells, colocalized with PD-L1 and PD-L2 in cSCC lesions. Conclusions and Relevance: The favorable treatment response combined with significant involvement of PD-1 and PD ligands in cSCC lesions suggests that PD-1 blockade may be a viable therapeutic option for locally advanced cSCC and provides rationale for further investigation in future clinical trials.

Cutaneous squamous cell carcinomas (SCCs) account for up to 10,000 deaths annually in the United States. Most of the more than 700,000 SCCs diagnosed are cured by excision with clear margins; however, metastasis can occur despite seemingly adequate treatment in some cases. Immune-suppressed organ transplant recipients are 60 to 100 times more likely to develop SCC than immune-competent individuals. Transplant-associated SCCs occur more frequently and behave more aggressively, showing higher risk of recurrence and metastasis. This article identifies a potential role for interleukin-22 in driving SCC proliferation, particularly in solid organ transplant recipients taking cyclosporine.

Basal cell carcinoma (BCC) is the most common human cancer with an estimate of over one million new cases diagnosed in the United States every year. Treatment for BCC is largely achieved by surgical excision, but there are select cases of locally aggressive BCC where surgery may be complicated by severe functional and cosmetic compromise. Other therapeutic options include vismod-egib, an FDA-approved smoothened inhibitor for treating advanced BCC patients, or immune activation with imiquimod. These options, however, are not effective for all BCC patients. By combining laser capture microdissection and cDNA microarray techniques, we have previously established gene expression profiling of BCC tumor nests (localized and infiltrative) as well as normal epidermis. We have demonstrated that anaplastic lymphoma kinase (ALK) was highly expressed in BCC and could be a potential therapeutic option for treating BCC. In this study, we investigated the expression of additional receptor tyrosine kinases in BCC, in addition to ALK. cDNA microarray analysis identified increased expression of AXL (FCH = 4.30, p<10~⁴), DDR1 (FCH = 3.27, p<10~⁴), NTRK3 (FCH = 38.26, p<10~⁴), and TRIM27 (FCH = 4.39, p<10~⁴). Protein expression of these molecules within tissues was also evaluated by immunohistochemistry. Although further functional analysis is required to assess the suitability of these receptor tyrosine kinases as therapeutic targets for BCC, identification of previously unrecognized molecules will facilitate developing new therapeutic strategy

Cancer testis antigens (CTAs) are tumor-associated antigens selectively expressed in human tumors, but not in normal tissues except for testis and placenta. CTAs possess strong immunogenic-ity, thus can be suitable molecular targets for cancer immune therapy. Squamous cell carcinoma (SCC) is a second most common skincancer.Although manycasesarecurablebysurgical treatment, recent studies have shown that the death rate for SCC approaches that for melanoma in parts of the United States. By combining laser capture microdissection and cDNA microarray techniques, we have previously established gene expression profiling of three distinct transformed keratinocytic regions (actinic keratosis, in situ SCC, and invasive SCC) as well as normal epidermis. We found that CTAs such as, MAGEA3, MAGEA4, and MAGEA6 were selectively up-regulated in invasive SCC, but not in actinic keratosis or in situ SCC compared to normal epidermis (fold change <3.0 and false discovery rate >0.05). The specific expression of MAGEA3 in invasive SCC wasconfirmedbyreverse transcription polymerase chain reaction for messenger RNA. Protein expression within the tissues was then examined by immunohistochemistry. Identification of new therapeutic target will facilitate developing new therapeutic strategy. Although further functional analysis is required to assess the suitability of these CTAs as therapeutic targets for SCC, our preliminary results suggest that cutaneous SCC can be a potential target of cancer immune therapy

Immune-suppressed organ transplant recipients (OTRs) can develop catastrophic squamous cell carcinoma (SCC), characterized by multiple primary tumors, extensive body surface area involvement, or metastases. There are currently no curative systemic therapies available. We previously showed that IL-22 enhances SCC proliferation. Herein, we examined links between cyclosporine (CSA), IL-22, and SCC in patients, cell lines, and mice with UV light-induced SCC. Eighteen of 114 OTRs developed catastrophic SCC, which was strongly associated with CSA treatment. We found that CSA drives T cell polarization toward IL-22-producing T22 cells, and CSA treatment increased IL-22 receptor in SCC cells. SCC tissue from OTRs showed increased expression of IL-22RA1. CSA potentiated rescue by IL-22 of serum-starved SCC cells; treatment of SCC cells with IL-22 and CSA increased both their migratory and invasive capacity. In a UV-induced model of SCC in SKH-1 immunocompetent mice, treatment with anti-IL-22 antibody reduced tumor number and tumor burden. We found that catastrophic SCC in OTRs is associated with CSA use, which may be acting by favoring T22 polarization. Since anti-IL-22 antibody administration decreased tumor number and tumor burden in vivo, blockade of the IL-22 axis may be developed as a viable therapeutic option for catastrophic SCC.