Presence of Skin Tissue-Resident Memory T Cells in Human Nonmalignant and Premalignant Melanocytic Skin Lesions and in Melanoma.

ABSTRACT: The infiltration of tissue-resident memory (TRM) cells in melanoma correlates with improved survival, suggesting an important role for TRM cells in immunity against melanoma. However, little is known about the presence of TRM cells in nonmalignant and premalignant melanocytic lesions. This study aimed to evaluate the presence of TRM cells in human skin melanocytic lesions, representing the spectrum from healthy skin to metastatic melanoma. FFPE sections from healthy skin, sun-exposed skin, benign nevi, lentigo maligna (LM), primary LM melanoma, and primary cutaneous and metastatic melanoma were analyzed by immunohistochemistry. The number of infiltrating cells expressing TRM-associated markers, CD3, CD4, CD8, CD69, CD103, and CD49a, was quantified by digital analyses. Multiplex immunofluorescence was performed to analyze coexpression of TRM cell markers. More T cells and CD69+ cells were found in melanoma lesions, as compared with healthy skin and nevi. CD103+ and CD49a+ cell numbers did not significantly differ. More importantly, no differences were seen in expression of all markers between healthy skin and benign nevi. Similar results, except for CD69, were observed in LM melanoma, as compared with LM and sun-exposed skin. Interestingly, multiplex immunofluorescence showed that nevi tissues have comparable CD103+ T cell numbers with healthy skin but comprise more CD103+ CD8+ cells. Expression of TRM cell markers is significantly increased in melanoma, as compared with nonmalignant skin. Our data also show that TRM cells are not abundantly present already in premalignant tissues. Further studies on the specificity of TRM cells for melanocyte/melanoma antigens may reveal their significance in cancer immunosurveillance.

Differential Expression of Cancer Testis Antigens on Lentigo Maligna and Lentigo Maligna Melanoma.

The cancer/testis antigens (CTA) are a group of antigens expressed on germ cells of healthy testis and malignant tumors. We studied whether CTA are present on lentigo maligna (LM) and LM melanoma (LMM) samples. Immunohistochemical expression of a panel of CTA (MAGE-A1, A2- A3, NY-ESO-1, PRAME, SSX-2, and a MAGE-A antibody reactive with -A1, -A2, -A3, -A4, -A6, -A10, and -A12) was investigated in formalin-fixed paraffin-embedded samples from LMM (n = 20), LM (n = 8), chronically sun-exposed skin (n = 7), and healthy skin (n = 7). In 4 LMM lesions, the MAGE-A marker was positive. Another 3 LMM lesions were positive for MAGE-A1, MAGE-A2, and MAGE-A3. PRAME was positive in 18/20 LMM and 6/8 LM. We did not find expression of MAGE, NY-ESO-1, or SSX-2 in LM, thereby excluding these CTA as diagnostic markers to discern malignant melanocytes in LM from normal melanocytes. LMM did express MAGE, NY-ESO-1, and SSX-2. If a biopsy from a lesion suspect for LM shows positivity for MAGE, NY-ESO-1, and SSX-2, the lesion may actually be LMM. In contrast, PRAME expression was found in LM at low levels and in LMM at much higher levels, and absent in normal melanocytes. PRAME can potentially be used to discern normal melanocytes from malignant melanocytes.

Effectiveness of 5% Topical Imiquimod for Lentigo Maligna Treatment.

Lentigo maligna (LM) is treated to prevent progression to lentigo maligna melanoma (LMM). Surgery is the gold standard but an alternative treatment is off-label topical imiquimod. The aim of this study was to evaluate the effectiveness of 5% topical imiquimod treatment for lentigo maligna. In the period 2007-2017 57 patients with lentigo maligna were treated with off-label topical imiquimod once daily for 12 weeks. Complete clinical clearance was observed in 48 patients (84.2%) and partial clearance in 3 patients (5.3%). Three patients (5.3%) showed no response and another 3 patients (5.3%) stopped treatment due to side-effects. After 4.5 years during follow-up one patient developed a lentigo maligna melanoma which was subsequently excised. Treatment with topical imiquimod resulted in complete clearance of lentigo maligna in 48 out of 57 patients (84.2%). Topical imiquimod is an acceptable treatment option for patients with lentigo maligna who prefer topical treatment to surgery or radiotherapy.

Close Surveillance with Long-Term Follow-up of Subjects with Preinvasive Endobronchial Lesions.

RATIONALE: Autofluorescence bronchoscopy (AFB) and computed tomography (CT) enable lung cancer (LC) detection at the early (pre-)invasive stage. However, LC risk in patients with preinvasive endobronchial lesions is unclear. OBJECTIVES: To assess LC incidence and identify potential risk determinants in patients with preinvasive lesions. METHODS: In our tertiary care referral center, 164 subjects with preinvasive lesions were monitored up to 12.5 years by repeated AFB and CT. Occurrence of LC was monitored. Clinical management depended on histological grade, with cancer patients receiving standard care. Potential risk determinants (smoking status, baseline histology, cancer history, and chronic obstructive pulmonary disease [COPD] status) were evaluated in relation to cancer occurrence, event-free survival (EFS), and overall survival (OS). MEASUREMENTS AND MAIN RESULTS: During surveillance (median of 30 mo, range 4-152) of 164 subjects with preinvasive lesions (80 high grade and 84 low grade at inclusion), 61 LCs were detected in 55 subjects (median time to event 16.5 mo). Twenty-three LCs (38%) were detected by CT, and 38 (62%) were detected by AFB. More cancers (36 of 61; 59%) developed from separate, rather than initial lesional sites. Subjects with high-grade lesions were more likely to be diagnosed with LC at the same or another site in the lungs than those with low-grade lesions (P = 0.03). Independent risk determinants for OS were previous curatively treated cancer and COPD (P ≤ 0.05). CONCLUSIONS: Presence of preinvasive lesions, especially high-grade lesions, may serve as LC risk markers. LCs occur both at preinvasive lesion sites and elsewhere in the bronchial epithelium or lung parenchyma. Prospective validation of biomarkers and randomized intervention studies are needed to determine optimal management strategies.

Cutaneous non-allergic complications in tattoos: An overview of the literature.

Tattooing is creating a permanent design by placing exogenous pigment particles and additives into the dermis. An adverse reaction may occur due to the act of tattooing and subsequent application of aftercare products. Numerous articles report the wide spectrum of adverse reactions related to tattooing, ranging from superficial infections and vasculitis to Koebner triggered autoimmune diseases. These reactions have different time of onset of symptoms, appearing immediately after placement of the tattoo until several years later. In this article we will give an overview of cutaneous non-allergic adverse reactions of tattoos.

Expression of cancer/testis antigens in cutaneous melanoma: a systematic review.

The cancer/testis antigen (CTA) family is a group of antigens whose expression is restricted to male germline cells of the testis and various malignancies. This expression pattern makes this group of antigens potential targets for immunotherapy. The aim of this study was to create an overview of CTA expressed by melanoma cells at mRNA and protein level. A systematic literature search was performed in Medline (PubMed) and Embase from inception up to and including February 2018. Studies were screened for eligibility by two independent reviewers. A total of 65 full-text articles were included in the final analysis. A total of 48 CTA have been studied in melanoma. Various CTA show different expression rates in primary and metastatic tumours. Of the 48 CTA, the most studied were MAGE-A3, MAGE-A1, NY-ESO-1, MAGE-A4, SSX2, MAGE-A2, MAGE-C1/CT7, SSX1, MAGE-C2/CT10 and MAGE-A12. On average, MAGE-A3 mRNA is present in 36% of primary tumours, whereas metastatic tumours have an expression rate of 55-81%. The same applies to the protein expression rate of MAGE-A3 in primary tumours, which is reported to be at 15-37%, whereas metastatic tumours have a higher expression rate of 25-70%. This trend of increased expression in metastases compared with primary tumours is observed with MAGE-A1, MAGE-A2, MAGE-A4, MAGE-A12 and NY-ESO-1. Many CTA are expressed on melanoma. This review provides an overview of the expression frequency of CTAs in melanoma and may aid in identifying CTA as the therapeutic target for immunotherapy.

Risk factors for hemoptysis in idiopathic and hereditary pulmonary arterial hypertension.

INTRODUCTION: When hemoptysis complicates pulmonary arterial hypertension (PAH), it is assumed to result from bronchial artery hypertrophy. In heritable PAH, the most common mutation is in the BMPR2 gene, which regulates growth, differentiation and apoptosis of mesenchymal cells. The aim of this study is to determine the relationship in PAH between the occurrence of hemoptysis, and disease progression, bronchial artery hypertrophy, pulmonary artery dilation and BMPR2 mutations. METHODS: 129 IPAH patients underwent baseline pulmonary imaging (CT angio or MRI) and repeated right-sided heart catheterization. Gene mutations were assessed in a subset of patients. RESULTS: Hemoptysis was associated with a greater presence of hypertrophic bronchial arteries and more rapid hemodynamic deterioration. The presence of a BMPR2 mutation did not predispose to the development of hemoptysis, but was associated with a greater number of hypertrophic bronchial arteries and a worse baseline hemodynamic profile. CONCLUSION: Hemoptysis in PAH is associated with bronchial artery hypertrophy and faster disease progression. Although the presence of a BMPR2 mutation did not correlate with a greater incidence of hemoptysis in our patient cohort, its association with worse hemodynamics and a trend of greater bronchial arterial hypertrophy may increase the risk of hemoptysis.