Search

Immunotherapy has achieved tremendous success in melanoma. However, only around 50% of advanced melanoma patients benefit from immunotherapy. Cyclin‐dependent kinase inhibitor 2A (CDKN2A), encoding the two tumor‐suppressor proteins p14ARF and p16INK4a, belongs to the most frequently inactivated gene loci in melanoma and leads to decreased T cell infiltration. While the role of p16INK4a has been extensively investigated, knowledge about p14ARF in melanoma is scarce. In this study, we elucidate the impact of reduced p14ARF expression on melanoma immunogenicity. Knockdown of p14ARF in melanoma cell lines diminished their recognition and killing by melanoma differentiation antigen (MDA)‐specific T cells. Resistance was caused by a reduction of the peptide surface density of presented MDAs. Immunopeptidomic analyses revealed that antigen presentation via human leukocyte antigen class I (HLA‐I) molecules was enhanced upon p14ARF downregulation in general, but absolute and relative expression of cognate peptides was decreased. However, this phenotype is associated with a favorable outcome for melanoma patients. Limiting Wnt5a signaling reverted this phenotype, suggesting an involvement of non‐canonical Wnt signaling. Taken together, our data indicate a new mechanism limiting MDA‐specific T cell responses by decreasing both absolute and relative MDA‐peptide presentation in melanoma. [ABSTRACT FROM AUTHOR]

However, there is still a considerable need for effective targeted therapies for other melanoma subgroups with constitutive MAPK activation, such as RAS- and NF-1-mutated tumors, as well as for therapeutic options targeting MAPK pathway inhibitor resistant BRAF-mutated melanomas, which commonly exhibit a striking reactivation of this pathway. Based on that, our work "Inhibition of RSK family members can effectively target malignant melanoma cells with MAPK pathway hyperactivation" assessed a potential functional role of the p90 ribosomal S6 kinases and their inhibition in different MAPK pathway-driven genetic melanoma subgroups. In line with a pronounced reactivation of the MAPK pathway in the case of MAPK pathway inhibitor resistance, we observed a further increase in RSK activity in BRAF-mutated melanoma cells with acquired MAPK pathway inhibitor resistance both in an in vitro model system and in tumor biopsies from stage IV melanoma patients which progressed under MAPK pathway inhibitor therapy. We found that IL-9-producing TH cells are better described as a subpopulation of TH2 cells that express IL-9 transiently post activation, rather than as a bona fide TH cell lineage. [Extracted from the article]

The BRAFV600E inhibitor vemurafenib achieves remarkable clinical responses in patients with BRAF-mutant melanoma, but its effects are limited by the onset of drug resistance. In the case of resistance, chemotherapy can still be applied as second line therapy. However, it yields low response rates and strategies are urgently needed to potentiate its effects. In a previous study, we showed that the inhibition of the PI3K- AKT- mTOR pathway significantly increases sensitivity of melanoma cells to chemotherapeutic drugs ( J. Invest. Dermatol. 2009, 129, 1500). In this study, the combination of the mTOR inhibitor temsirolimus with the chemotherapeutic agent temozolomide significantly increases growth inhibition and apoptosis in melanoma cells compared to temsirolimus or temozolomide alone. The combination of temozolomide with temsirolimus is not only effective in established but also in newly isolated and vemurafenib-resistant metastatic melanoma cell lines. These effects are associated with the downregulation of the anti-apoptotic protein Mcl-1 and the upregulation of the Wnt antagonist Dickkopf homologue 1 ( DKK1). Knock-down of DKK1 suppresses apoptosis induction by the combination of temsirolimus and temozolomide. These data suggest that the inhibition of the mTOR pathway increases sensitivity of melanoma cells towards temozolomide. Chemosensitisation is associated with enhanced expression of the Wnt antagonist DKK1. [ABSTRACT FROM AUTHOR]