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Individual ability to produce interleukin-10 (IL-10) may be of relevance in the development and evolution of cutaneous melanoma, probably due to its immunosuppressor and anti-angiogenic properties. Single nucleotide polymorphisms at positions -1082 (G/A), -819 (C/T) and -592 (C/A) in the IL-10 gene promoter were analysed in 100 healthy individuals and 98 melanoma patients using fluorogenic hybridization-specific probes in a 'real-time' thermocycler. Polymorphic frequencies were correlated with various prognostic factors and overall survival. The frequency of IL-10 polymorphic variants was similar in patients and controls. However, high producer genotypes at the -1082 position were over-represented in males with an older age at diagnosis. The analysis of the promoter genotypes in patients stratified according to clinical prognostic factors did not show any associations, although a trend (not statistically significant) towards a prolonged survival in patients genotyped as high IL-10 producers was observed. In addition, the low producer -1082AA genotype was significantly associated with decreased survival in patients with advanced disease. Similarly, the presence of this genotype shortened the overall survival in males after recurrence or metastasis development. In conclusion, the frequency of genetic variants in the IL-10 gene promoter was not associated with melanoma appearance, but conditioned the age at diagnosis in males and the overall survival in patients with advanced disease.

Although immune checkpoint blockade (ICB) has shown remarkable clinical benefit in a subset of patients with melanoma and lung cancer, most patients experience no durable benefit. The receptor tyrosine kinase AXL is commonly implicated in therapy resistance and may serve as a marker for therapy-refractory tumors, for example in melanoma, as we previously demonstrated. Here, we show that enapotamab vedotin (EnaV), an antibody–drug conjugate targeting AXL, effectively targets tumors that display insensitivity to immunotherapy or tumor-specific T cells in several melanoma and lung cancer models. In addition to its direct tumor cell killing activity, EnaV treatment induced an inflammatory response and immunogenic cell death in tumor cells and promoted the induction of a memory-like phenotype in cytotoxic T cells. Combining EnaV with tumor-specific T cells proved superior to either treatment alone in models of melanoma and lung cancer and induced ICB benefit in models otherwise insensitive to anti–PD-1 treatment. Our findings indicate that targeting AXL-expressing, immunotherapy-resistant tumors with EnaV causes an immune-stimulating tumor microenvironment and enhances sensitivity to ICB, warranting further investigation of this treatment combination. Significance: These findings show that targeting AXL-positive tumor fractions with an antibody–drug conjugate enhances antitumor immunity in several humanized tumor models of melanoma and lung cancer.

-rearranged acute lymphoblastic leukemia (ALL) occurring in infants is a rare but very aggressive leukemia, typically associated with a dismal prognosis. Despite the development of specific therapeutic protocols, infant patients with -rearranged ALL still suffer from a low cure rate. At present, novel therapeutic approaches are urgently needed. Recently, the use of small molecule inhibitors targeting the epigenetic regulators of the MLL complex emerged as a promising strategy for the development of a targeted therapy. Herein, we have investigated the effects of bromodomain and extra-terminal (BET) function abrogation in a preclinical mouse model of MLL-AF4 infant ALL using the BET inhibitor I-BET151. We reported that I-BET151 is able to arrest the growth of MLL-AF4 leukemic cells , by blocking cell division and rapidly inducing apoptosis. Treatment with I-BET151 impairs the leukemic engraftment of patient-derived primary samples and lower the disease burden in mice. I-BET151 affects the transcriptional profile of -rearrangedALL through the deregulation of , and gene networks. Moreover, I-BET151 treatment sensitizes glucocorticoid-resistant -rearranged cells to prednisolone and is more efficient when used in combination with HDAC inhibitors, both and Given the aggressiveness of the disease, the failure of the current therapies and the lack of an ultimate cure, this study paves the way for the use of BET inhibitors to treat -rearranged infant ALL for future clinical applications..