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- Efimova, I, et al.
(författare)
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Vaccination with early ferroptotic cancer cells induces efficient antitumor immunity
- 2020
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Ingår i: Journal for immunotherapy of cancer. - : BMJ. - 2051-1426. ; 8:2
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Tidskriftsartikel (refereegranskat)abstract
- Immunotherapy represents the future of clinical cancer treatment. The type of cancer cell death determines the antitumor immune response and thereby contributes to the efficacy of anticancer therapy and long-term survival of patients. Induction of immunogenic apoptosis or necroptosis in cancer cells does activate antitumor immunity, but resistance to these cell death modalities is common. Therefore, it is of great importance to find other ways to kill tumor cells. Recently, ferroptosis has been identified as a novel, iron-dependent form of regulated cell death but whether ferroptotic cancer cells are immunogenic is unknown.MethodsFerroptotic cell death in murine fibrosarcoma MCA205 or glioma GL261 cells was induced by RAS-selective lethal 3 and ferroptosis was analyzed by flow cytometry, atomic force and confocal microscopy. ATP and high-mobility group box 1 (HMGB1) release were detected by luminescence and ELISA assays, respectively. Immunogenicity in vitro was analyzed by coculturing of ferroptotic cancer cells with bone-marrow derived dendritic cells (BMDCs) and rate of phagocytosis and activation/maturation of BMDCs (CD11c+CD86+, CD11c+CD40+, CD11c+MHCII+, IL-6, RNAseq analysis). The tumor prophylactic vaccination model in immune-competent and immune compromised (Rag-2−/−) mice was used to analyze ferroptosis immunogenicity.ResultsFerroptosis can be induced in cancer cells by inhibition of glutathione peroxidase 4, as evidenced by confocal and atomic force microscopy and inhibitors’ analysis. We demonstrate for the first time that ferroptosis is immunogenic in vitro and in vivo. Early, but not late, ferroptotic cells promote the phenotypic maturation of BMDCs and elicit a vaccination-like effect in immune-competent mice but not in Rag-2−/− mice, suggesting that the mechanism of immunogenicity is very tightly regulated by the adaptive immune system and is time dependent. Also, ATP and HMGB1, the best-characterized damage-associated molecular patterns involved in immunogenic cell death, have proven to be passively released along the timeline of ferroptosis and act as immunogenic signal associated with the immunogenicity of early ferroptotic cancer cells.ConclusionsThese results pave the way for the development of new therapeutic strategies for cancers based on induction of ferroptosis, and thus broadens the current concept of immunogenic cell death and opens the door for the development of new strategies in cancer immunotherapy.
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| 2. |
- Krysko, O, et al.
(författare)
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Artificial Intelligence Predicts Severity of COVID-19 Based on Correlation of Exaggerated Monocyte Activation, Excessive Organ Damage and Hyperinflammatory Syndrome: A Prospective Clinical Study
- 2021
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Ingår i: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 12, s. 715072-
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Tidskriftsartikel (refereegranskat)abstract
- Prediction of the severity of COVID-19 at its onset is important for providing adequate and timely management to reduce mortality.ObjectiveTo study the prognostic value of damage parameters and cytokines as predictors of severity of COVID-19 using an extensive immunologic profiling and unbiased artificial intelligence methods.MethodsSixty hospitalized COVID-19 patients (30 moderate and 30 severe) and 17 healthy controls were included in the study. The damage indicators high mobility group box 1 (HMGB1), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), extensive biochemical analyses, a panel of 47 cytokines and chemokines were analyzed at weeks 1, 2 and 7 along with clinical complaints and CT scans of the lungs. Unbiased artificial intelligence (AI) methods (logistic regression and Support Vector Machine and Random Forest algorithms) were applied to investigate the contribution of each parameter to prediction of the severity of the disease.ResultsOn admission, the severely ill patients had significantly higher levels of LDH, IL-6, monokine induced by gamma interferon (MIG), D-dimer, fibrinogen, glucose than the patients with moderate disease. The levels of macrophage derived cytokine (MDC) were lower in severely ill patients. Based on artificial intelligence analysis, eight parameters (creatinine, glucose, monocyte number, fibrinogen, MDC, MIG, C-reactive protein (CRP) and IL-6 have been identified that could predict with an accuracy of 83−87% whether the patient will develop severe disease.ConclusionThis study identifies the prognostic factors and provides a methodology for making prediction for COVID-19 patients based on widely accepted biomarkers that can be measured in most conventional clinical laboratories worldwide.
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| 3. |
- Krysko, O, et al.
(författare)
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Many faces of DAMPs in cancer therapy
- 2013
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 4, s. e631-
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Tidskriftsartikel (refereegranskat)
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| 6. |
- Krysko, O, et al.
(författare)
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Severity of SARS-CoV-2 infection is associated with high numbers of alveolar mast cells and their degranulation
- 2022
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Ingår i: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 13, s. 968981-
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Tidskriftsartikel (refereegranskat)abstract
- The systemic inflammatory response post-SARS-CoV-2 infection increases pro-inflammatory cytokine production, multi-organ damage, and mortality rates. Mast cells (MC) modulate thrombo-inflammatory disease progression (e.g., deep vein thrombosis) and the inflammatory response post-infection.ObjectiveTo enhance our understanding of the contribution of MC and their proteases in SARS-CoV-2 infection and the pathogenesis of the disease, which might help to identify novel therapeutic targets.MethodsMC proteases chymase (CMA1), carboxypeptidase A3 (CPA3), and tryptase beta 2 (TPSB2), as well as cytokine levels, were measured in the serum of 60 patients with SARS-CoV-2 infection (30 moderate and 30 severe; severity of the disease assessed by chest CT) and 17 healthy controls by ELISA. MC number and degranulation were quantified by immunofluorescent staining for tryptase in lung autopsies of patients deceased from either SARS-CoV-2 infection or unrelated reasons (control). Immortalized human FcεR1+c-Kit+ LUVA MC were infected with SARS-CoV-2, or treated with its viral proteins, to assess direct MC activation by flow cytometry.ResultsThe levels of all three proteases were increased in the serum of patients with COVID-19, and strongly correlated with clinical severity. The density of degranulated MC in COVID-19 lung autopsies was increased compared to control lungs. The total number of released granules and the number of granules per each MC were elevated and positively correlated with von Willebrand factor levels in the lung. SARS-CoV-2 or its viral proteins spike and nucleocapsid did not induce activation or degranulation of LUVA MC in vitro.ConclusionIn this study, we demonstrate that SARS-CoV-2 is strongly associated with activation of MC, which likely occurs indirectly, driven by the inflammatory response. The results suggest that plasma MC protease levels could predict the disease course, and that severe COVID-19 patients might benefit from including MC-stabilizing drugs in the treatment scheme.
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