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Glioma-associated microglia/macrophages (GAM) represent an attractive therapeutic target for the development of the alternative methodology in the treatment of gliomas. This study was aimed to investigate the effect of intranasally administered TLR3 agonist Larifan on microglial cell metabolic profile in rats with C6 glioma. Our results demonstrate progressive generation microglial cell population with immunosuppressive and pro-inflammatory properties in C6 glioma-bearing brain. Intranasally delivered TLR3 agonist is capable to abrogate the creation of this pro-tumoral immune infiltrates, probably, through the effect on myeloid-derived suppressor cells, and can be considered as a promising agent for glioma therapy aimed the GAM re-education.

Neuroblastoma is one of the most common cancers in children that arises from sympathetic nervous system tissue with a high rate of incidence in Ukraine. Genetic abnormalities containing loss of chromosome 1p36 and 11q, MYCN amplification are strongly associated with poor prognosis of this disease. Despite rare TP53 mutations, p53 pathway is often inactivated in neuroblastoma, mostly by MDM2 overexpression. Members of miR-34 microRNA family are the most prevalent p53-induced miRNAs and important mediators of tumor suppression. MiR-34 microRNA family consists of three members: miR-34a is encoded by its own transcript from 1p36, whereas miR-34b and miR-34c share a common primary transcript in 11q. It is suggested that miR-34a is a suppressor of neuroblastoma tumor genesis, as it targets many oncogenes such as E2F3, BCL-2 and MYCN. In this study, we present evidence of miR-34 deregulation in neuroblastoma. A decrease of miR-34 expression was associated with unfavorable clinical and biological features of the disease. Low miR-34a expression was associated with a decrease of survival rates in groups of patients with MDM2 overexpression and MYCN not-amplified low expressed MDM2 neuroblastoma. Taking this into account, analysis of mir-34a expression can help to improve personalized therapy strategy and serve as additional marker for the stratification optimization in patients with neuroblastoma.

The article describes the phenotypic and functional properties of human dendritic cells generated after treatment with cytotoxic lectins B. subtilis B-7025.

Neuroblastoma is the most common extracranial malignant solid tumor in children. This disease displays a remarkable heterogeneity in clinical behavior, ranging from spontaneous regression to rapid progression and resistance to therapy. Recent evidence has shown that microRNAs are often involved in regulation of tumor development and progression. MiR-885-5p has a tumor suppressive role in neuroblastoma, interfe­ring with cell cycle progression and cell survival. MiR-885-5p leads to the accumulation of p53 protein and activates p53-mediated pathway of cell cycle arrest, resulting in upregulation of its targets. We have analyzed association of miR-885-5p expression in 58 neuroblastoma tumors with different clinical characteristics and disease outcome. In tumor samples of patients with unfavorable clinical characteristics lower miR-885-5p expression levels were observed. Event-free survival analysis showed that low miR-885-5p expression was tightly associated with a significantly poorer outcome than in those with high expression of miR-885-5p. In this study, evidence is presented on miR-885-5p dysregulation in neuroblastoma. As follows, along with other clinical features, it can be used as an independent prognostic and possibly therapeutic approach for optimization of neuroblastoma treatment.

Oncolytic peptides are derived from natural host defense peptides/antimicrobial peptides produced in a wide variety of life forms. Over the past two decades, they have attracted much attention in both basic research and clinical applications. Oncolytic peptides were expected to act primarily on tumor cells and also trigger the immunogenic cell death. Their ability in the tumor microenvironment remodeling and potentiating the anticancer immunity has long been ignored. Despite the promising results, clinical application of oncolytic peptides is still hindered by their unsatisfactory bioactivity and toxicity to normal cells. To ensure safer therapy, various approaches are being developed. The idea of the Ukrainian research group was to equip peptide molecules with a "molecular photoswitch" - a diarylethene fragment capable of photoisomerization, allowing for the localized photoactivation of peptides within tumors reducing side effects. Such oncolytic peptides that may induce the membrane lysis-mediated cancer cell death and subsequent anticancer immune responses in combination with the low toxicity to normal cells have provided a new paradigm for cancer therapy. This review gives an overview of the broad effects and perspectives of oncolytic peptides in anticancer immunity highlighting the potential issues related to the use of oncolytic peptides in cancer immunotherapy. We summarize the current status of research on peptide-based tumor immunotherapy in combination with other therapies including immune checkpoint inhibitors, chemotherapy, and targeted therapy.

Glioblastoma (GBM) is the most aggressive primary malignant brain tumor in adults. The improvement of the efficacy of GBM treatment is an urgent problem encouraging the development of novel therapeutic strategies, in particular, immunotherapeutic modalities. With more understanding of the intimate interrelationships between the immune system and the mechanisms involved in cancer origin and progression, the skepticism related to the relevance of the immunotherapeutic approaches in the treatment of brain tumors is gradually decreasing. The review discloses the modern concepts on the association between CNS and the immune system. For a long time, CNS was considered as the immunoprivileged site that prevents the effects of immunotherapy in the treatment of brain tumors. Nowadays, these views are reconsidered, which opens the way to the use of immunotherapeutic approaches in GBM treatment. The results of the recent clinical trials on immunotherapy as a supplement to the conventional GBM treatment are considered. Vaccines based on the dendritic cell (DC) technology are regarded as the most promising for this purpose. The preliminary results of the Ukrainian clinical study are also presented and discussed. The results of the international clinical trials as well as our own experience give evidence of the relevance for using DC vaccines in the complex treatment of GBM, which is supported by the increased survival of patients and the safety of vaccine application. It is of high importance that GBM patients with the most unfavorable prognosis can benefit from DC vaccines as a component of the complex treatment. The prospects for immunotherapy in neurooncology are discussed.

The search for new prognostic and stratification genetic and epigenetic markers in neuroblastoma is an urgent problem in pediatric oncology. The review summarizes recent progress in studying the expression of genes involved in p53 pathway regulation in neuroblastoma. Several markers associated with recurrence risk and poor outcome are considered. Among them are MYCN amplification, high MDM2 and GSTP1 expression and homozygous mutant allele variant of GSTP1 gene A313G polymorphism. Prognostic criteria for neuroblastoma based on the analysis of miR-34a, miR-137, miR-380-5p, and miR-885-5p expression involved in regulating p53-mediated pathway are also considered. The authors' research data on the role of the above markers in regulation of this pathway in neuroblastoma are presented. The study of alterations in expression of microRNAs and genes involved in p53 pathway regulation will not only expand our understanding of the mechanisms of neuroblastoma pathogenesis but could substantiate new approaches for delineating risk groups and risk stratification of neuroblastoma patients as well as treatment optimization based on the genetic characteristics of the tumor.

Purpose: The gene BRCA1 plays a key role in DNA repair in breast and ovarian cell lines and this is considered one of target tumor suppressor genes in same line of cancers. The 5382insC mutation is among the most frequently detected in patients (Eastern Europe) with triple-negative breast cancer (TNBC). In Ukraine, there is not enough awareness of necessity to test patients with TNBC for BRCA1 mutations. That is why this group of patients is not well-studied, even through is known the mutation may affect the course of disease., Methods: The biological samples of 408 female patients were analyzed of the 5382insC mutation in BRCA1. We compared the frequency of the 5382insC mutation in BRCA1 gene observed in Ukraine with known frequencies in other countries., Results: For patients with TNBC, BRCA1 mutations frequency was 11.3%, while in patients with luminal types of breast cancers, the frequency was 2.8%. Prevalence of 5382insC among TNBC patients reported in this study was not different from those in Tunisia, Poland, Russia, and Bulgaria, but was higher than in Australia and Germany., Conclusion: The BRCA1 c.5382 mutation rate was recorded for the first time for TNBC patients in a Ukrainian population. The results presented in this study underscore the importance of this genetic testing of mutations in patients with TNBC. Our study supports BRCA1/2 genetic testing for all women diagnosed with TNBC, regardless of the age of onset or family history of cancer and not only for women diagnosed with TNBC at <60y.o., as guidelines recommend., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: One of the major factors restricting in vivo efficacy of dendritic cells (DCs) based immunotherapy is the inefficient migration of these cells to the lymphoid tissue, wherein DCs activate antigen-specific T cells. A fundamentally new approach for the possibility of enhancing the antitumor effects of DC-based immunotherapy may be the use of magnetically sensitive nanocomplexes to increase the target delivery of DCs to the lymph nodes of the recipient., Aim: To study the antitumor and immunomodulatory effects of the DC-nanovaccine with magnetosensitive properties and its influence on the immunosuppressive tumor microenvironment in mice with sarcoma 37., Materials and Methods: The antitumor, antimetastatic and immunomodulatory effects of DCs loaded with magnetic nanocomplex under magnetic field (MF) control in mice with sarcoma 37 have been investigated., Results: Combined therapy contributed to a significant reduction in tumor volume and weight compared to the control group of mice and mice that received the DC vaccine without MF. Therapy with magnetically sensitive DC nanovaccine with and without the addition of the MF was accompanied by a significant down-regulation of the level of FoxP3, transforming growth factor β, interleukin (IL)-10 and vascular endothelial growth factors, mRNA expression in tumor tissues. A significant increase in interferon-γ and IL-4 mRNA expression was found in mice treated with the magnetically sensitive DC nanovaccine under MF control., Conclusion: A significant increase in the antitumor efficacy of the DC vaccine can be achieved using magnetosensitive nanocarriers of tumor antigens under MF control.

Background: Clinical outcomes of Langerhans cell histiocytosis (LCH) are highly variable. It has been suggested that mitogen-activated protein kinase (MAPK) /extracellular signal-regulated kinases (ERK) signaling pathway might be activated in LCH patients., Materials and Methods: We investigated KRAS, BRAF and NRAS mutations in patients with LCH by qPCR., Results: Eight adult patients with LCH were treated at the National Cancer Institute, Kiev, Ukraine. Five patients received chemo plus radiation therapy and three patients received only chemotherapy, resp. (p < 0.05). All patients received LCH-I study protocol, six cycles in average. A BRAF c.1799T > A, p. V600E mutation was detected in 25% (2/8) of cases - 1 patient had an early relapse in 6 months, and 1 patient - stable disease. We did not find any BRAF, KRAS or NRAS mutations in three patients with late relapses (in 15, 24 and 46 months). Notably, KRAS mutations were not revealed in any LCH samples. The NRAS c.182A > G, p. Q61R mutation was found in two cases - one patient had LCH transformed to Hodgkins lymphoma, one patient had a refractory disease. Time to relapse rate (TTR) in patients with and without BRAF V600E gene mutation was 13 vs. 28 months, resp. (p < 0.05). TTR was 31.3 vs. 6.41 months in patients with absence and presence of NRAS mutation, p < 0.05. Multivariate analysis showed the presence of NRAS Q61R mutation was associated with poor event-free survival in LCH patients with HR of 6.1 (95% CI 0.2-12.6; p = 0.008)., Conclusion: BRAF and NRAS mutations in LCH suggest a possibility of the disease being driven by the activation of the MAPK/ERK pathway. These oncogenic mutations provide new opportunities in understanding LCH pathogenesis and may be a potential target of therapy.Key words: Langerhans cell histiocytosis - mutations - prognostic factors - relapse - survival.

Purpose: Tumor cell resistance to platinum-based chemotherapeutic agents is one of the major hurdles to successful cancer treatment with these drugs, and is associated with alterations in tumor cell immune evasion and immunomodulatory properties. Immunocyte targeting is considered as a relevant approach to fight drug-resistant cancer. In this study, immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells (LLC/R9) were investigated., Methods: Immunological features of LLC/R9 cells cultured in vitro in normoxic and hypoxic conditions as well as of those that were grown in vivo were examined. The expression of immunologically relevant genes was evaluated by RT-PCR. Tumor cell susceptibility to the macrophage contact tumoricidal activity and NK-mediated cytolysis was investigated in MTT test. TNF-α-mediated tumor cell apoptosis as well as macrophage phagocytosis, oxidative metabolism, and CD206 expression after the treatment with conditioned media from normoxic and hypoxic tumor cells were studied by flow cytometry. Flow cytometry was also used to characterize dendritic cell maturity., Results: When growing in vitro, LLC/R9 were characterized by slightly increased immunosuppressive cytokine gene expression. Transition to in vivo growth was associated with the enhancement of transcription of these genes in tumor cells. LLC/R9 cells had lowered sensitivity to contact-dependent macrophage-mediated cytotoxicity and to the TNFα-mediated apoptosis in vitro. Conditioned media from hypoxic LLC/R9 cells stimulated reactive oxygen species generation and CD206 expression in non-sensitized macrophages. Acquisition of drug resistance by LLC/R9 cells was associated with their increased sensitivity to NK-cell-mediated cytolysis. Meanwhile, the treatment of LLCR/9-bearing animals with generated ex vivo and loaded with LLC/R9 cell-lysate dendritic cells (DCs) resulted in profoundly enhanced tumor metastasizing., Conclusion: Decreased sensitivity to macrophage cytolysis, polarizing effect on DCs maturation along with increased susceptibility to NK-cell cytotoxic action promote extensive local growth of chemoresistant LLC/R9 tumors in vivo, but hamper their metastasizing.

Ovarian cancer is the seventh most common cancer in women worldwide and the leading cause of gynecological malignant diseases-related deaths in women. The most significant risk factor for ovarian cancer is an inherited genetic mutation in one of two genes: breast cancer gene 1 (BRCA1) or breast cancer gene 2 (BRCA2). The germline mutation c.5266dupC (also known as 5382insC or 5385insC) is the most common mutation among Slavic patients with breast and/or ovarian cancer. Missense mutation c.181T > G (also known as 300T > G or p.C61G) is regarded as the founder change in many Central European countries. We screened 306 ovarian cancer patients diagnosed at different ages by mutagenically separated polymerase chain reaction (PCR) and real-time PCR. A total of 25 BRCA1 mutations were detected (18 cases of 5382insC and 7 cases of 300 T > G). The frequency of the BRCA1 5382insC mutation is similar in breast and ovarian cancer patients from Ukraine, but the frequency of 300T > G was estimated in Ukraine at first time.

Background and Aim: Human beta-defensin-2 (hBD-2) is an antimicrobial cationic peptide capable to control human carcinoma cell growth via cell cycle regulation. The present study was aimed on determination of hBD-2 influence on the growth patterns and malignant potential of cultured human melanoma cells., Methods: The study was performed on cultured human melanoma cells of mel Z and mel Is lines treated with recombinant hBD-2 (rec-hBD-2); cell viability, proliferation, cell cycle distribution, and anchorage-independent growth were analyzed using MTT test, direct cell counting, flow cytometry, and colony forming assay respectively. Expression and/or phosphorylation levels of proteins involved in cell cycle control were evaluated by Western blotting., Results: The treatment of mel Z and mel Is cells with rec-hBD-2 in a concentration range of 100-1000 nM resulted in a concentration-dependent suppression of cell proliferation, viability, and colony forming activity. It has been shown that rec-hBD-2 exerts its growth suppression effects via significant downregulation of B-Raf expression, activation of pRB and upregulation of p21(WAF1) expression, downregulation of cyclin D1 and cyclin E resulting in cell cycle arrest at G1/S checkpoint., Conclusion: According to obtained results, hBD-2 exerts its growth suppression effect toward human melanoma cells via downregulation of B-Raf, cyclin D1 and cyclin E expression, upregulation of p21(WAF1) expression and activation of pRB.