Background: Autologous dendritic cells (DC) loaded with tumor-associated antigens (TAAs) are a promising approach for anticancer immunotherapy. Polyantigen lysates appear to be an excellent source of TAAs for loading onto the patient's dendritic cells. Cancer/testis antigens (CTA) are expressed by a wide range of tumors, but are minimally expressed on normal tissues, and could serve as a universal target for immunotherapy. However, CTA expression levels can vary significantly in patients with the same tumor type. We proposed that patients who do not respond to DC-based therapy may have distinct features of the CTA expression profile on tumor cells. Patients and methods: We compared the gene expression of the principal families CTA in 22 melanoma and 27 soft tissue and bone sarcomas cell lines (STBS), received from patients and used for DC vaccine preparation. Results: The majority (47 of 49, 95.9%) cell lines showed CTA gene activity. The incidence of gene expression of GAGE, NYESO1, MAGEA1, PRAME's was significantly different (adj. p < 0.05) between melanoma and sarcoma cell lines. The expression of the SCP1 gene was detected neither in melanoma cells nor in the STBS cells. Clustering by the gene expression profile revealed four different expression patterns. We found three main patterns types: hyperexpression of multiple CTA, hyperexpression of one CTA with almost no expression of others, and no expression of CTA. All clusters types exist in melanoma and sarcoma cell lines. We observed dependence of killing efficacy from the PRAME (rho = 0.940, adj. p < 0.01) expression during real-time monitoring with the xCELLigence system of the interaction between melanoma or sarcoma cells with the T-lymphocytes activated by the lysate of selected allogenous melanoma cell lines with high expression of CTA. Conclusion: Our results demonstrate that one can use lysates from allogeneic melanoma cell lines as a source of CTA for DC load during the production of anticancer vaccines for the STBS treatment. Patterns of CTA expression should be evaluated as biomarkers of response in prospective clinical trials.

The increasing incidence of melanoma makes this cancer an important public health problem. Therapeutic resistance is still a major obstacle to the therapy of patients with metastatic melanomas. The aim of this study was to develop the melanoma cell line resistant to DNA-alkylating agents and to elucidate the mechanisms involved in acquired drug resistance. We established a unique melanoma subline Mel MeR resistant to DNA-alkylating drug aranoza by continuous stepwise selection of the Mel Me/WT cell line with increasing concentrations of this drug. Mel MeR cells were also cross-resistant to streptozotocin or cisplatin. Here, we show that aranoza-resistant melanoma cells modulate the ABC transporter activity, upregulate the expression of PRAME, adopt a vascular-related phenotype and engage in vasculogenic mimicry. LCS1269, a vasculogenic mimicry low-molecular-weight inhibitor, reverses the sensitivity of resistant melanoma cells to DNA-damaging agents. In this study, we provide experimental evidence that LCS1269 might be considered as a new potential anticancer agent capable of overcoming multidrug resistance for DNA-damaging agents in melanoma.

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Apoptosis can be triggered from external signals. Several homologous receptors transmit apoptotic signals from outside into the cell. For successful activation of apoptosis receptors should interact with their ligands. For example, FAS receptor must bind with FAS-ligand, TNFR1 with TNFα, TRAIL-R1 and TRAIL-R2 with TRAIL, DR3 - with TL1A, respectively. In majority of cases ligands should be anchoring in the cell membrane to perform their functions. FAS and TNFR1 receptors trigger apoptosis only when they are internalized into the cell’s cytoplasm. If FAS and TNFR1 are not internalized, then anti-apoptotic program won’t start. In contrast, TRAIL-R1, TRAIL-R2 and DR3 aren’t internalized during apoptotic signal transduction. Other receptors, TNFR2, TRAIL-R3 and TRAIL-R4 start an anti-apoptotic program. The apoptotic signal starts when DISC complex is formed on the inner side of the cell membrane. FADD, procaspase-8 and intracellular domain of receptor form together DISC complex. If the DISC complex wasn’t formed, signal is transmitted by the NFкB-way via MAP-kinase cascade. In such conditions anti-apoptotic program starts. A variety of receptors and ligands provides for multiple biological functions. For example, receptor-mediated apoptosis takes a part in elimination of infected or transformed cells, regulation of inflammation, modulation of ontogenesis, hematopoiesis and antibody production.