"PRIMUS/MED/12"
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Renal cell carcinoma (RCC) is one of the most lethal urologic malignancies. Its incidence continues to rise worldwide with a rate of 2% per year. Approximately, one-third of the RCC patients are diagnosed at advanced stages due to the asymptomatic nature of its early stages. This represents a great hurdle, since RCC is largely chemoresistant/radioresistant, and targeted therapy of mRCC still has limited efficacy. The 5-year survival rate of metastatic RCC (mRCC) is only around 10%. Adoptive cell transfer (ACT), a particular form of cell-based anticancer immunotherapy, is a promising approach in the treatment of mRCC. The vaccination principle, however, faces unique challenges that preclude the efficacy of ACT. In this article, we review the main challenges of ACT in the treatment of mRCC and describe multiple methods that can be used to overcome these challenges. In this respect, the ultimate purpose of this review is to provide a descriptive tool by which to improve the development of novel protocols for ACT of mRCC.
- MeSH
- imunoterapie metody MeSH
- karcinom z renálních buněk patologie MeSH
- lidé MeSH
- míra přežití MeSH
- nádory ledvin patologie MeSH
- převzatá imunita metody MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
PURPOSE: Esophageal cancer (EC) is one of the most lethal gastrointestinal malignancies. Immunotherapy is a promising treatment modality for this disease. However, broader implementation of EC immunotherapy has been discouraged because of insufficient understanding of tumor interactions with the immune system. As with other malignancies, the current research on EC focuses on deciphering the immune cell signatures within the tumor microenvironment. However, the disease-elicited immune cell profiles in the paratumoral compartments are largely unknown. METHODS: We examined the immune cell signatures in 62 tissue samples from 16 EC patients in different esophageal tissue compartments: tumor tissue, peritumoral tissue, healthy esophageal tissue, and adjacent lymph nodes. We analyzed the proportions and distribution patterns of NK cells and CD4+ and CD8+ T cells as well as their death receptor (FasR, FasR/DR3)-expressing subpopulations. The analyzed data were then compared and correlated with the patients' clinicopathological data. RESULTS: We found that the FasR+ NK cells, CD4+ and CD8+ T cells infiltrated lymph nodes at the lowest levels and that the FasR+DR3+ CD4+ T cells were enhanced in tumors. The comparisons with the clinicopathological data revealed a major impact of active smoking on the reduction in paratumoral NK cells and the upregulation of FasR in tumor-infiltrating NK and CD8+ T cells. The lymph node metastatic stage, tumor stage, and Mandard grade correlated with the compartmental proportions of the evaluated immune cells. CONCLUSION: The novel association of the disease state with tumoral and paratumoral immune cell signatures suggests new possibilities for personalized immunotherapy for EC patients.
- MeSH
- adenokarcinom imunologie patologie terapie MeSH
- antigeny CD95 imunologie MeSH
- buňky NK imunologie patologie MeSH
- CD4-pozitivní T-lymfocyty imunologie patologie MeSH
- CD8-pozitivní T-lymfocyty imunologie patologie MeSH
- imunoterapie metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfatické uzliny imunologie patologie MeSH
- lymfocyty imunologie patologie MeSH
- nádory jícnu imunologie patologie terapie MeSH
- senioři MeSH
- skvamózní karcinom jícnu imunologie patologie terapie MeSH
- studie případů a kontrol MeSH
- T-lymfocyty - podskupiny imunologie patologie MeSH
- tumor infiltrující lymfocyty imunologie patologie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
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.
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.
- 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
Salivary gland carcinomas (SGCs) are extremely morphologically heterogeneous, and treatment options for this disease are limited. Immunotherapy with immune checkpoint inhibitors (ICIs) represents a revolutionary treatment approach. However, SGCs remain largely resistant to this therapy. An increasing body of evidence suggests that resistance to ICI therapy is modulated by the Fas (CD95)-Fas ligand (FasL, CD178) interplay between tumor cells and immune cells. In this study, we examined the Fas-FasL interplay between tumor cells and tumor-infiltrating immune cells (TIICs) in the center and periphery of SGCs from 62 patients. We found that the Fas-expressing tumor cells accumulated in the center of SGC tumors with increasing tumor stage. Furthermore, this accumulation occurred regardless of the presence of TIICs expressing high levels of FasL. On the contrary, a loss of Fas-expressing TIICs with increasing tumor stage was found in the tumor periphery, whereas FasL expression in tumor cells in the tumor periphery correlated with tumor stage. These data suggest that SGC cells are resistant to FasL-induced apoptosis by TIICs but could utilize FasL to eliminate these cells in high-stage tumors to provide resistance to immunotherapy.
- Publikační typ
- časopisecké články MeSH
CD8+ T cells protect against tumors and intracellular pathogens. The inflammatory cytokines IL-2, IL-15, and IL-7 are necessary for their expansion. However, elevated serum levels of these cytokines are often associated with cancer, poorer prognosis of cancer patients, and exhaustion of antigen-expanded CD8+ T cells. The impact of acute conditioning of antigen-expanded CD8+ T cells with these cytokines is unknown. Here, we generated antigen-expanded CD8+ T cells using dendritic cells and PC-3 cells. The cells were acutely (18-24 h) conditioned with IL-2 and either the GSK3β inhibitor TWS119, the mTORC1 inhibitor rapamycin, or the mTORC1/2 inhibitor Torin1, then their immediate and post-re-expansion (distal) cytokine responses after antigen rechallenge were evaluated. We found that acute IL-2 conditioning upregulated the immediate antigen-induced cytokine response of the tested cells. Following their re-expansion, however, the cells showed a decreased cytokine response. These IL-2 conditioning-mediated impacts were counteracted with TWS119 or rapamycin but not with Torin1. Our data revealed that the acute conditioning of antigen-expanded CD8+ T cells with IL-2 modulates the GSK3β-mTORC signaling axis. This modulation differentially affected the immediate and distal cytokine responses of the cells. The acute targeting of this signaling axis could, therefore, represent a novel strategy for the modulation of antigen-expanded CD8+ T cells.
- Publikační typ
- časopisecké články MeSH
