Ex vivo-produced dendritic cells (DCs) constitute the core of active cellular immunotherapy (ACI) for cancer treatment. After many disappointments in clinical trials, the current protocols for their preparation are attempting to boost their therapeutic efficacy by enhancing their functionality towards Th1 response and capability to induce the expansion of cytotoxic tumor-specific CD8+ T cells. LL-37 is an antimicrobial peptide with strong immunomodulatory potential. This potential was previously found to either enhance or suppress the desired anti-tumor DC functionality when used at different phases of their ex vivo production. In this work, we show that LL-37 can be implemented during the whole process of DC production in a way that allows LL-37 to enhance the anti-tumor functionality of produced DCs. We found that the supplementation of LL-37 during the differentiation of monocyte-derived DCs showed only a tendency to enhance their in vitro-induced lymphocyte enrichment with CD8+ T cells. The supplementation of LL-37 also during the process of DC antigen loading (pulsation) and maturation significantly enhanced the cell culture enrichment with CD8+ T cells. Moreover, this enrichment was also associated with the downregulated expression of PD-1 in CD8+ T cells, significantly higher frequency of tumor cell-reactive CD8+ T cells, and superior in vitro cytotoxicity against tumor cells. These data showed that LL-37 implementation into the whole process of the ex vivo production of DCs could significantly boost their anti-tumor performance in ACI.

• Klíčová slova
• CD8+ T cells, LL-37, cancer, cellular immunotherapy, dendritic cells,
• Publikační typ
• časopisecké články MeSH

The immune checkpoint inhibitors have revolutionized cancer immunotherapy. These inhibitors are game changers in many cancers and for many patients, sometimes show unprecedented therapeutic efficacy. However, their therapeutic efficacy is largely limited in many solid tumors where the tumor-controlled immune microenvironment prevents the immune system from efficiently reaching, recognizing, and eliminating cancer cells. The tumor immune microenvironment is largely orchestrated by immune cells through which tumors gain resistance against the immune system. Among these cells are mast cells and dendritic cells. Both cell types possess enormous capabilities to shape the immune microenvironment. These capabilities stage these cells as cellular checkpoints in the immune microenvironment. Regaining control over these cells in the tumor microenvironment can open new avenues for breaking the resistance of solid tumors to immunotherapy. In this review, we will discuss mast cells and dendritic cells in the context of solid tumors and how these immune cells can, alone or in cooperation, modulate the solid tumor resistance to the immune system. We will also discuss how this modulation could be used in novel immunotherapeutic modalities to weaken the solid tumor resistance to the immune system. This weakening could then help other immunotherapeutic modalities engage against these tumors more efficiently.

• Klíčová slova
• cellular checkpoint, dendritic cells, immunotherapy, mast cells,
• MeSH
• dendritické buňky patologie   MeSH
• imunoterapie MeSH
• inhibitory kontrolních bodů MeSH
• lidé MeSH
• mastocyty * patologie   MeSH
• nádorové mikroprostředí MeSH
• nádory * patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• inhibitory kontrolních bodů MeSH

BACKGROUND: Most patients with epithelial ovarian cancer (EOC) relapse despite primary debulking surgery and chemotherapy (CT). Autologous dendritic cell immunotherapy (DCVAC) can present tumor antigens to elicit a durable immune response. We hypothesized that adding parallel or sequential DCVAC to CT stimulates antitumor immunity and improves clinical outcomes in patients with EOC. Based on the interim results of sequential DCVAC/OvCa administration and to accommodate the increased interest in maintenance treatment in EOC, the trial was amended by adding Part 2. METHODS: Patients with International Federation of Gynecology and Obstetrics stage III EOC (serous, endometrioid, or mucinous), who underwent cytoreductive surgery up to 3 weeks prior to randomization and were scheduled for first-line platinum-based CT were eligible. Patients, stratified by tumor residuum (0 or <1 cm), were randomized (1:1:1) to DCVAC/OvCa parallel to CT (Group A), DCVAC/OvCa sequential to CT (Group B), or CT alone (Group C) in Part 1, and to Groups B and C in Part 2. Autologous dendritic cells for DCVAC were differentiated from patients' CD14+ monocytes, pulsed with two allogenic OvCa cell lines (SK-OV-3, OV-90), and matured in the presence of polyinosinic:polycytidylic acid. We report the safety outcomes (safety analysis set, Parts 1 and 2 combined) along with the primary (progression-free survival (PFS)) and secondary (overall survival (OS)) efficacy endpoints. Efficacy endpoints were assessed in the modified intention-to-treat (mITT) analysis set in Part 1. RESULTS: Between November 2013 and March 2016, 99 patients were randomized. The mITT (Part 1) comprised 31, 29, and 30 patients in Groups A, B, and C, respectively. Baseline characteristics and DCVAC/OvCa exposure were comparable across the treatment arms. DCVAC/OvCa showed a good safety profile with treatment-emergent adverse events related to DCVAC/OvCa in 2 of 34 patients (5.9%) in Group A and 2 of 53 patients (3.8%) in Group B. Median PFS was 20.3, not reached, and 21.4 months in Groups A, B, and C, respectively. The HR (95% CI) for Group A versus Group C was 0.98 (0.48 to 2.00; p=0.9483) and the HR for Group B versus Group C was 0.39 (0.16 to 0.96; p=0.0336). This was accompanied by a non-significant trend of improved OS in Groups A and B. Median OS was not reached in any group after a median follow-up of 66 months (34% of events). CONCLUSIONS: DCVAC/OvCa and leukapheresis was not associated with significant safety concerns in this trial. DCVAC/OvCa sequential to CT was associated with a statistically significant improvement in PFS in patients undergoing first-line treatment of EOC. TRIAL REGISTRATION NUMBER: NCT02107937, EudraCT2010-021462-30.

• Klíčová slova
• clinical trials, dendritic cells, immunotherapy, phase II as topic,
• MeSH
• acetylcystein analogy a deriváty   MeSH
• dendritické buňky imunologie   MeSH
• dospělí MeSH
• epiteliální ovariální karcinom farmakoterapie   MeSH
• imunoterapie metody   MeSH
• karboplatina farmakologie   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• myši MeSH
• paclitaxel farmakologie   terapeutické užití   MeSH
• protokoly antitumorózní kombinované chemoterapie farmakologie   terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• myši MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• acetylcystein MeSH
• karboplatina MeSH
• paclitaxel MeSH
• S-1,2-dichlorovinyl-N-acetylcysteine MeSH Prohlížeč

INTRODUCTION: The COVID-19 vaccine was designed to provide protection against infection by the severe respiratory coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19). However, the vaccine's efficacy can be compromised in patients with immunodeficiencies or the vaccine-induced immunoprotection suppressed by other comorbidity treatments, such as chemotherapy or immunotherapy. To enhance the protective role of the COVID-19 vaccine, we have investigated a combination of the COVID-19 vaccination with ex vivo enrichment and large-scale expansion of SARS-CoV-2 spike glycoprotein-reactive CD4+ and CD8+ T cells. METHODS: SARS-CoV-2-unexposed donors were vaccinated with two doses of the BNT162b2 SARS-CoV-2 vaccine. The peripheral blood mononuclear cells of the vaccinated donors were cell culture-enriched with T cells reactive to peptides derived from SARS-CoV-2 spike glycoprotein. The enriched cell cultures were large-scale expanded using the rapid expansion protocol (REP) and the peptide-reactive T cells were evaluated. RESULTS: We show that vaccination with the SARS-CoV-2 spike glycoprotein-based mRNA COVID-19 vaccine-induced humoral response against SARS-CoV-2 spike glycoprotein in all tested healthy SARS-CoV-2-unexposed donors. This humoral response was found to correlate with the ability of the donors' PBMCs to become enriched with SARS-CoV-2 spike glycoprotein-reactive CD4+ and CD8+ T cells. Using an 11-day REP, the enriched cell cultures were expanded nearly 1000-fold, and the proportions of the SARS-CoV-2 spike glycoprotein-reactive T cells increased. CONCLUSION: These findings show for the first time that the combination of the COVID-19 vaccination and ex vivo T cell large-scale expansion of SARS-CoV-2-reactive T cells could be a powerful tool for developing T cell-based adoptive cellular immunotherapy of COVID-19.

• Klíčová slova
• COVID-19 vaccination, SARS-CoV-2, cellular immunity, ex vivo expansion, humoral immunity, spike glycoprotein-reactive,
• MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• COVID-19 * imunologie   MeSH
• glykoprotein S, koronavirus imunologie   MeSH
• glykoproteiny MeSH
• leukocyty mononukleární MeSH
• lidé MeSH
• protilátky virové MeSH
• SARS-CoV-2 MeSH
• vakcína BNT162 MeSH
• vakcíny proti COVID-19 * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• glykoprotein S, koronavirus MeSH
• glykoproteiny MeSH
• protilátky virové MeSH
• spike protein, SARS-CoV-2 MeSH Prohlížeč
• vakcína BNT162 MeSH
• vakcíny proti COVID-19 * MeSH

The preparation of dendritic cells (DCs) for adoptive cellular immunotherapy (ACI) requires the maturation of ex vivo-produced immature(i) DCs. This maturation ensures that the antigen presentation triggers an immune response towards the antigen-expressing cells. Although there is a large number of maturation agents capable of inducing strong DC maturation, there is still only a very limited number of these agents approved for use in the production of DCs for ACI. In seeking novel DC maturation agents, we used differentially activated human mast cell (MC) line LAD2 as a cellular adjuvant to elicit or modulate the maturation of ex vivo-produced monocyte-derived iDCs. We found that co-culture of iDCs with differentially activated LAD2 MCs in serum-containing media significantly modulated polyinosinic:polycytidylic acid (poly I:C)-elicited DC maturation as determined through the surface expression of the maturation markers CD80, CD83, CD86, and human leukocyte antigen(HLA)-DR. Once iDCs were generated in serum-free conditions, they became refractory to the maturation with poly I:C, and the LAD2 MC modulatory potential was minimized. However, the maturation-refractory phenotype of the serum-free generated iDCs was largely overcome by co-culture with thapsigargin-stimulated LAD2 MCs. Our data suggest that differentially stimulated mast cells could be novel and highly potent cellular adjuvants for the maturation of DCs for ACI.

• Klíčová slova
• LAD2 human mast cells, adoptive cellular immunotherapy, dendritic cells, maturation,
• MeSH
• adjuvancia imunologická farmakologie   MeSH
• buněčná diferenciace účinky léků   MeSH
• buněčné kultury metody   MeSH
• dendritické buňky cytologie   účinky léků   imunologie   MeSH
• imunoterapie adoptivní * MeSH
• kokultivační techniky MeSH
• lidé MeSH
• mastocyty cytologie   účinky léků   imunologie   MeSH
• monocyty cytologie   účinky léků   imunologie   MeSH
• prezentace antigenu účinky léků   imunologie   MeSH
• thapsigargin farmakologie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adjuvancia imunologická MeSH
• thapsigargin MeSH

Dendritic cells (DCs) are key regulators of immune responses that operate at the interface between innate and adaptive immunity, and defects in DC functions contribute to the pathogenesis of a variety of disorders. For instance, cancer evolves in the context of limited DC activity, and some autoimmune diseases are initiated by DC-dependent antigen presentation. Thus, correcting aberrant DC functions stands out as a promising therapeutic paradigm for a variety of diseases, as demonstrated by an abundant preclinical and clinical literature accumulating over the past two decades. However, the therapeutic potential of DC-targeting approaches remains to be fully exploited in the clinic. Here, we discuss the unique features of DCs that underlie the high therapeutic potential of DC-targeting strategies and critically analyze the obstacles that have prevented the full realization of this promising paradigm.

• Klíčová slova
• autoimmune disorders, cancer, dendritic cells, immunotherapy, vaccine preparation,
• MeSH
• antigen prezentující buňky imunologie   metabolismus   MeSH
• autoimunita MeSH
• autoimunitní nemoci etiologie   metabolismus   terapie   MeSH
• buněčná diferenciace genetika   imunologie   MeSH
• dendritické buňky imunologie   metabolismus   MeSH
• imunita * MeSH
• imunologická tolerance * MeSH
• imunoterapie MeSH
• lidé MeSH
• mezibuněčná komunikace MeSH
• náchylnost k nemoci MeSH
• nádory etiologie   metabolismus   patologie   terapie   MeSH
• plasticita buňky genetika   imunologie   MeSH
• prezentace antigenu imunologie   MeSH
• protinádorové vakcíny aplikace a dávkování   imunologie   MeSH
• T-lymfocyty imunologie   metabolismus   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• protinádorové vakcíny MeSH

Similarly to other types of malignant tumours, the incidence of head and neck cancer is increasing globally. It is frequently associated with smoking and alcohol abuse, and in a broader sense also with prolonged exposure to these factors during ageing. A higher incidence of tumours observed in younger populations without a history of alcohol and tobacco abuse may be due to HPV infection. Malignant tumours form an intricate ecosystem of cancer cells, fibroblasts, blood/lymphatic capillaries and infiltrating immune cells. This dynamic system, the tumour microenvironment, has a significant impact on the biological properties of cancer cells. The microenvironment participates in the control of local aggressiveness of cancer cells, their growth, and their consequent migration to lymph nodes and distant organs during metastatic spread. In cancers originating from squamous epithelium, a similarity was demonstrated between the cancer microenvironment and healing wounds. In this review, we focus on the specificity of the microenvironment of head and neck cancer with emphasis on the mechanism of intercellular crosstalk manipulation for potential therapeutic application.

• Klíčová slova
• IL-6, cancer, cancer ecosystem, cancer microenvironment, cancer therapy, cancer-associated fibroblast, cytokine, extracellular matrix, tumour-associated macrophages,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Upregulated Wnt/β-catenin signaling is associated with increased cancer cell resistance and cancer cell-elicited immunosuppression. In non-neoplastic immune cells, upregulated Wnt/β-catenin is, however, associated with either immunosuppression or immunostimulation. Therefore, it is difficult to predict the therapeutic impact inhibitors of Wnt/β-catenin signaling will have when combined with cancer immunotherapy. Here, we evaluated the benefit(s) of the Wnt/β-catenin signaling inhibitor XAV939 in the in vitro elimination of LNCaP prostate cancer cells when cocultured with lymphocytes from patients with localized biochemically recurrent prostate cancer (BRPCa). We found that 5 µM XAV939 inhibited β-catenin translocation to the nucleus in LNCaP cells and CD4+ BRPCa lymphocytes without affecting their proliferation and viability. Preconditioning BRPCa lymphocytes with 5 µM XAV939 accelerated the elimination of LNCaP cells during the coculturing. However, during subsequent re-coculturing with fresh LNCaP cells, BRPCa lymphocytes were no longer able to eliminate LNCaP cells unless coculturing and re-coculturing were performed in the presence of 5 µM XAV939. Comparable results were obtained for PC-3 prostate cancer cells. These findings provide a rationale for combining cell-based immunotherapy of PCa with inhibitors of Wnt/β-catenin signaling.

• MeSH
• antitumorózní látky farmakologie   MeSH
• beta-katenin antagonisté a inhibitory   metabolismus   MeSH
• buňky PC-3 MeSH
• CD4-pozitivní T-lymfocyty účinky léků   imunologie   MeSH
• heterocyklické sloučeniny tricyklické farmakologie   MeSH
• imunoterapie metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prostaty farmakoterapie   genetika   patologie   MeSH
• proteiny Wnt antagonisté a inhibitory   metabolismus   MeSH
• senioři MeSH
• signální dráha Wnt účinky léků   MeSH
• T-lymfocyty cytologie   imunologie   MeSH
• tankyrasy antagonisté a inhibitory   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• beta-katenin MeSH
• CTNNB1 protein, human MeSH Prohlížeč
• heterocyklické sloučeniny tricyklické MeSH
• proteiny Wnt MeSH
• tankyrasy MeSH
• XAV939 MeSH Prohlížeč

Personalized peptide vaccination is a promising immunotherapeutic approach in prostate cancer (PCa). We therefore examined whether an approach, utilizing personalized multiple peptide-mediated ex vivo enrichment with effector T cells reactive to multiple tumor-associated antigens (TAAs), could be employed as a basis for the development of T cell immunotherapy of PCa. In this study, we used the non-adherent fraction (lymphocytes) of cryopreserved peripheral blood mononuclear cells from a leukapheretic product of biochemically recurrent (BR, n = 14) and metastatic hormone-refractory (HR, n = 12) PCa patients. The lymphocytes were primed with a pool of mixed overlapping peptides derived from 6 PCa TAAs-PSA, PAP, NY-ESO-1, MAGE-A1, MAGE-A3 and MAGE-A4. After 2 weeks of culture, the cells were stimulated with the peptides and T cell reactivity determined by externalization of CD107a. No TAAs-reactive effector T cells were detected in the patient's lymphocytes after their reconstitution. However, following their priming with the TAAs-derived peptides and 2-week culturing, the lymphocytes became enriched with polyclonal TAAs-reactive effector CD8+ T cells in 8 out of 14 BR and 5 out of 12 HR patients. No such reactive CD8+ T cells were detected in cultured lymphocytes without the peptide priming. Stimulation of the responding cultures with peptides derived from individual TAAs revealed a unique repertoire of the reactive CD8+ T cells. Our strategy revealed that the personalized multiple peptide-mediated ex vivo enrichment with multiple TAAs-reactive T cells in the PCa patient's lymphocytes is a viable approach for development of T cell immunotherapy of PCa.

• Klíčová slova
• CD107a externalization, Personalized T cell immunotherapy, Prostate cancer, Tumor-associated antigens,
• MeSH
• antigeny nádorové imunologie   MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• imunoterapie metody   MeSH
• individualizovaná medicína metody   MeSH
• kalikreiny imunologie   MeSH
• kultivované buňky MeSH
• leukocyty mononukleární imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• melanomové antigeny imunologie   MeSH
• membránové proteiny imunologie   MeSH
• nádorové proteiny imunologie   MeSH
• nádory prostaty imunologie   patologie   MeSH
• peptidy imunologie   MeSH
• prostatický specifický antigen imunologie   MeSH
• senioři MeSH
• T-lymfocyty imunologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny nádorové MeSH
• CTAG1B protein, human MeSH Prohlížeč
• kalikreiny MeSH
• KLK3 protein, human MeSH Prohlížeč
• MAGEA1 protein, human MeSH Prohlížeč
• MAGEA3 protein, human MeSH Prohlížeč
• MAGEA4 protein, human MeSH Prohlížeč
• melanomové antigeny MeSH
• membránové proteiny MeSH
• nádorové proteiny MeSH
• peptidy MeSH
• prostatický specifický antigen MeSH