Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment, promoting tumor initiation, growth, progression, metastasis, and immune evasion. Recently it was shown that cancer cell-derived exosomes induce a tumor-promoting phenotype in TAMs. Exosome-loaded proteins, DNA, and RNAs may contribute to the macrophage reprogramming. However, the exact mediators and mechanisms, particularly in melanoma, are not known. In this study we examined the effects of cutaneous melanoma-derived exosomes on macrophage function and the underlying mechanisms. First, we showed that exposure to melanoma exosomes induces a tumor-promoting TAM phenotype in macrophages. Sequencing revealed enrichment for several miRNAs including miR-125b-5p in cutaneous melanoma exosomes. We showed that miR-125b-5p is delivered to macrophages by melanoma exosomes and partially induces the observed tumor-promoting TAM phenotype. Finally, we showed that miR-125b-5p targets the lysosomal acid lipase A (LIPA) in macrophages, which in turn contributes to their phenotype switch and promotes macrophage survival. Thus, our data show for the first time that miR-125b-5p transferred by cutaneous melanoma-derived exosomes induces a tumor-promoting TAM phenotype in macrophages.

Many melanomas are associated with activating BRAF mutation. Targeted therapies by inhibitors of BRAF and MEK (BRAFi, MEKi) show marked antitumor response, but become limited by drug resistance. The mechanisms for this are not fully revealed, but include miRNA. Wishing to improve efficacy of BRAFi and knowing that certain miRNAs are linked to resistance to BRAFi, we wanted to focus on miRNAs exclusively associated with response to BRAFi. We found increased expression of miR-129-5p during BRAFi treatment of BRAF- mutant melanoma cells. Parallel to emergence of resistance we observed mir-129-5p expression to become suppressed by BRAF/EZH2 signaling. In functional analyses we revealed that miR-129-5p acts as a tumor suppressor as its overexpression decreased cell proliferation, improved treatment response and reduced viability of BRAFi resistant melanoma cells. By protein expression analyses and luciferase reporter assays we confirmed SOX4 as a direct target of mir-129-5p. Thus, modulation of the miR-129-5p-SOX4 axis could serve as a promising novel strategy to improve response to BRAFi in melanoma.

Metastatic primary cutaneous melanoma is a frequently fatal disease despite recent therapeutic advances. Biomarkers to stratify patients’ prognosis are lacking. MicroRNAs (miRNAs) are small, non-coding RNAs. We aimed to determine the expression of miR-211-5p in primary tumors and metastases of malignant melanoma and its potential use as a prognostic biomarker. We performed in situ hybridization for miRNA-211-5p on 109 FFPE melanoma samples from 76 patients, including 31 paired primary tumor/metastasis samples. For validation, we performed in silico analyses of TCGA skin cutaneous melanoma (SKCM) cohort. High miR-211-5p expression was more frequent in primary tumors (70.8%) compared to metastases (39.3%). In metastases, it was associated with a significantly worse overall survival. Data from TCGA SKCM cohort confirmed that high miR-211-5p expression in melanoma metastases, but not primary tumors, is associated with worse overall survival. MiR-211-5p expression in metastases is associated with a shorter survival, emphasizing the potential of miR-211-5p as a risk predictor for a less favorable clinical outcome in metastatic disease. In situ hybridization could be implemented in a routine laboratory workflow and can be performed on diagnostic tissue.

Summary: Background: For patients with locally advanced (la) or metastatic (m) cutaneous squamous cell carcinoma (cSCC) who are not candidates for curative surgery/radiation or systemic anti‐PD1 therapy, anti‐EGFR in combination with chemotherapy is a rational treatment option.Patients and Methods: We analyzed data from 20 patients with cSCC in this monocentric, retrospective study. 4/20 patients had laSCC and 16/20 patients had mSCC. Patients received combined cetuximab and 5‐FU between 2015 and 2023. Nine patients received cetuximab + 5‐FU as second‐line therapy (8 patients after anti‐PD‐1, 1 patient after radiochemotherapy).Results: One patient had partial response (PR) and 9/20 (45.0%) had stable disease (SD). Disease control rate (PR + SD) was 50%. No complete remissions were observed. One of the non‐responders suffered from laSCC, nine patients had mSCC with distant metastases (including parotid) and locoregional lymph node metastases. Treatment was well tolerated, with a median PFS of 3 months (95% confidence interval [CI] 2 months to not assessable [NA]) and median overall survival (OS) of 29 months (95% CI 11–NA). The most common adverse event was acne‐like rash in 40.0% of patients.Conclusions: For patients with advanced cSCC who are contraindicated to or have progressed on first‐line cemiplimab, combination of cetuximab and 5‐FU is a well‐tolerated but limited treatment option.

Summary: Background and Objectives: Patients with cutaneous lymphomas (CL) are at an increased risk of developing secondary malignancies. This study aimed to assess the frequency of association between CL and Kaposi sarcoma (KS) and to identify factors that may promote the co‐occurrence of these two diseases. Patients and Methods: On January 25, 2024, we conducted a systematic search of four electronic medical databases to identify all published cases of KS associated with CL. The clinical course and outcomes of these patients were summarized. For critical appraisal, we applied the JBI Checklist for Case Reports. The study was registered in the PROSPERO database (CRD42022313204). Results: A total of 40 articles reporting on 45 patients were assessed for eligibility. We included 27 cases in the final analysis (26 cutaneous T‐cell lymphomas, 1 cutaneous B‐cell lymphoma). In 71% of cases, the diagnosis of CL preceded KS. Nearly half (48%) of the patients had erythrodermic mycosis fungoides or Sézary syndrome. KS lesions were predominantly limited to the skin, with complete remission achieved in 53% of cases. Conclusions: The association between KS and CL is rare, limiting our study due to the small sample size and potential reporting bias. Skin‐targeted therapies, a restricted T‐cell repertoire, and impaired T‐cell responses in erythrodermic CTCL patients may contribute to the development of KS.