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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..

Highlights Drug library screening identified pyrvinium to be effective against MLL -rearranged AML. Pyrvinium targets the mitochondria of MLL -rearranged AML cells. Pyrvinium does not antagonize with standard chemotherapy in MLL -rearranged AML.

Doxorubicin (doxo) remains the standard of care for patients with advanced soft tissue sarcoma (STS), even though response rates to doxo are only around 14% to 18%. We evaluated enapotamab vedotin (EnaV), an AXL-specific antibody-drug conjugate (ADC), in a panel of STS patient-derived xenografts (PDX). Eight models representing multiple STS subtypes were selected from our STS PDX platform (n = 45) by AXL immunostaining on archived passages. Models were expanded by unilateral transplantation of tumor tissue into the left flank of 20 NMRI nu/nu mice. Once tumors were established, mice were randomized into an EnaV treatment group, or a group treated with isotype control ADC. Treatment efficacy was assessed by tumor volume evaluation, survival analysis, and histological evaluation of tumors, and associated with AXL expression. EnaV demonstrated significant tumor growth delay, regression, and/or prolonged survival compared to isotype control ADC in 5/8 STS PDX models investigated. Experimental passages of responding models were all found positive for AXL at varying levels, but no linear relationship could be identified between the level of expression and level of response to EnaV. One model was found negative for AXL on experimental passage and did not respond to EnaV. This study provides a preclinical rationale for the evaluation of AXL-targeting ADCs in the treatment of AXL-expressing sarcomas.

Infants with MLL-rearranged infant acute lymphoblastic leukemia (MLL-r iALL) undergo intense therapy to counter a highly aggressive malignancy with survival rates of only 30–40%. The majority of patients initially show therapy response, but in two-thirds of cases the leukemia returns, typically during treatment. The glucocorticoid drug prednisone is established as a major player in the treatment of leukemia and the in vivo response to prednisone monotreatment is currently the best indicator of risk for MLL-r iALL. We used two different single-cell RNA sequencing technologies to analyze the expression of a prednisone-dependent signature, derived from an independent study, in diagnostic bone marrow and peripheral blood biopsies. This allowed us to classify individual leukemic cells as either resistant or sensitive to treatment and show that quantification of these two groups can be used to better predict the occurrence of future relapse in individual patients. This work also sheds light on the nature of the therapy-resistant subpopulation of relapse-initiating cells. Leukemic cells associated with high relapse risk are characterized by basal activation of glucocorticoid response, smaller size, and a quiescent gene expression program with cell stemness properties. These results improve current risk stratification and elucidate leukemic therapy-resistant subpopulations at diagnosis.