RESUMO
The ability of tumor-derived extracellular vesicles (EVs) to modulate the function of myeloid cells is widely recognized. Hence, a comprehensive understanding of the distinct components associated with EVs and the signals that they deliver to myeloid cells could provide potential approaches to impede the immunosuppression by myeloid-derived suppressor cells (MDSCs). We investigated melanoma EV-associated microRNAs (miRs) using the RET transgenic melanoma mouse model and simulated their transfer to normal myeloid cells by transfecting immature mouse myeloid cells and human monocytes. We observed elevated levels of miR-125a-5p, -125b-5p, and let-7e-5p in mouse melanoma-infiltrating MDSCs. In addition, miR-125a-5p levels in the tumor microenvironment correlated with mouse melanoma progression. The delivery of miR-125a-5p, alone or in combination with let-7e-5p and miR-99b-5p from the same genomic cluster, to normal myeloid cells resulted in their conversion to MDSC-like cells. Our findings indicate that miR-125a-5p could modulate myeloid cell activation in the melanoma microenvironment via a NF-κB-dependent mechanism.
Assuntos
Melanoma , MicroRNAs , Células Supressoras Mieloides , Microambiente Tumoral , MicroRNAs/genética , MicroRNAs/metabolismo , Células Supressoras Mieloides/metabolismo , Animais , Humanos , Camundongos , Microambiente Tumoral/genética , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Camundongos Transgênicos , NF-kappa B/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Camundongos Endogâmicos C57BL , Monócitos/metabolismoRESUMO
Anticancer agents continue to dominate the list of newly approved drugs, approximately half of which are immunotherapies. This trend illustrates the considerable promise of cancer treatments that modulate the immune system. However, the immune system is complex and dynamic, and can have both tumour-suppressive and tumour-promoting effects. Understanding the full range of immune modulation in cancer is crucial to identifying more effective treatment strategies. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells that develop in association with chronic inflammation, which is a hallmark of cancer. Indeed, MDSCs accumulate in the tumour microenvironment, where they strongly inhibit anticancer functions of T cells and natural killer cells and exert a variety of other tumour-promoting effects. Emerging evidence indicates that MDSCs also contribute to resistance to cancer treatments, particularly immunotherapies. Conversely, treatment approaches designed to eliminate cancer cells can have important additional effects on MDSC function, which can be either positive or negative. In this Review, we discuss the interplay between MDSCs and various other cell types found in tumours as well as the mechanisms by which MDSCs promote tumour progression. We also discuss the relevance and implications of MDSCs for cancer therapy.
Assuntos
Células Supressoras Mieloides , Neoplasias , Humanos , Células Supressoras Mieloides/metabolismo , Neoplasias/patologia , Células Mieloides/metabolismo , Células Mieloides/patologia , Imunoterapia , Linfócitos T , Microambiente TumoralRESUMO
Treatment with immune checkpoint inhibitors (ICIs) has improved the prognosis of melanoma patients. However, ICIs can cause an overactivation of the immune system followed by diverse immunological side effects known as immune-related adverse events (irAE). Currently, the toxicity of irAE is limiting the usage of ICIs. Here, we studied circulating monocytic myeloid-derived suppressor cells (M-MDSCs) and T cells in course of irAE after the ICI therapy. Our longitudinal study involved 31 melanoma patients with and without adverse events during anti-PD-1 monotherapy or anti-CTLA-4/PD-1 combination therapy. Peripheral blood samples were analyzed before ICI start, during ICI treatment, at the time point of irAE and during immunosuppressive treatment to cure irAE. We observed an enhanced progression-free survival among patients with irAE. In patients with irAE, we found an upregulation of CD69 on CD8+ T cells and a decreased frequency of regulatory T cells (Tregs). Moreover, lower frequencies of Tregs correlated with more severe side effects. Patients treated with immunomodulatory drugs after irAE manifestation tend to show an elevated number of M-MDSCs during an immunosuppressive therapy. We suggest that an activation of CD8+ T cells and the reduction of Treg frequencies could be responsible for the development of irAE.
Assuntos
Melanoma , Células Supressoras Mieloides , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Linfócitos T CD8-Positivos , Estudos Longitudinais , Melanoma/tratamento farmacológico , FenótipoRESUMO
Despite the remarkable success of immune checkpoint inhibitors (ICIs) in melanoma treatment, resistance to them remains a substantial clinical challenge. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of myeloid cells that can suppress antitumor immune responses mediated by T and natural killer cells and promote tumor growth. They are major contributors to ICI resistance and play a crucial role in creating an immunosuppressive tumor microenvironment. Therefore, targeting MDSCs is considered a promising strategy to improve the therapeutic efficacy of ICIs. This Review describes the mechanism of MDSC-mediated immune suppression, preclinical and clinical studies on MDSC targeting, and potential strategies for inhibiting MDSC functions to improve melanoma immunotherapy.
Assuntos
Melanoma , Células Supressoras Mieloides , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Imunoterapia , Células Matadoras Naturais/patologia , Microambiente TumoralRESUMO
BACKGROUND: Coronary care units are sophisticated clinics established to reduce deaths due to acute cardiovascular events. Current data on coronary care unit mortality rates and predictors of mortality in Turkey are very limited. The MORtality predictors in CORonary care units in TURKey (MORCOR-TURK) trial was designed to provide information on the mortality rates and predictors in patients followed in coronary care units in Turkey. METHODS: The MORCOR-TURK trial will be a national, observational, multicenter, and noninterventional study conducted in Turkey. The study population will include coronary care unit patients from 50 centers selected from all regions in Turkey. All consecutive patients admitted to coronary care units with cardiovascular diagnoses between 1 and 30 September 2022 will be prospectively enrolled. All data will be collected at one point in time, and the current clinical practice will be evaluated (ClinicalTrials.gov number NCT05296694). In the first step of the study, admission diagnoses, demographic characteristics, basic clinical and laboratory data, and in-hospital management will be assessed. At the end of the first step, the predictors and rates of in-hospital mortality will be documented. The second step will be in cohort design, and discharged patients will be followed up till 1 year. Predictors of short- and long-term mortality will be assessed. Moreover, a new coronary care unit mortality score will be generated with data acquired from this cohort. RESULTS: The short-term outcomes of the study are planned to be shared by early 2023. CONCLUSION: The MORCOR-TURK trial will be the largest and most comprehensive study in Turkey evaluating the rates and predictors of in-hospital mortality of patients admitted to coronary care units.
Assuntos
Mortalidade Hospitalar , Pacientes , Humanos , Hospitalização , Alta do Paciente , Turquia/epidemiologia , Unidades de Cuidados Coronarianos/estatística & dados numéricos , Estudos Multicêntricos como Assunto , Estudos Observacionais como Assunto , Cardiopatias/mortalidade , Cardiopatias/terapiaRESUMO
A gradual decay in humoral and cellular immune responses over time upon SAR1S-CoV-2 vaccination may cause a lack of protective immunity. We conducted a longitudinal analysis of antibodies, T cells, and monocytes in 25 participants vaccinated with mRNA or ChAdOx1-S up to 12 weeks after the 3rd (booster) dose with mRNA vaccine. We observed a substantial increase in antibodies and CD8 T cells specific for the spike protein of SARS-CoV-2 after vaccination. Moreover, vaccination induced activated T cells expressing CD69, CD137 and producing IFN-γ and TNF-α. Virus-specific CD8 T cells showed predominantly memory phenotype. Although the level of antibodies and frequency of virus-specific T cells reduced 4-6 months after the 2nd dose, they were augmented after the 3rd dose followed by a decrease later. Importantly, T cells generated after the 3rd vaccination were also reactive against Omicron variant, indicated by a similar level of IFN-γ production after stimulation with Omicron peptides. Breakthrough infection in participants vaccinated with two doses induced more SARS-CoV-2-specific T cells than the booster vaccination. We found an upregulation of PD-L1 expression on monocytes but no accumulation of myeloid cells with MDSC-like immunosuppressive phenotype after the vaccination. Our results indicate that the 3rd vaccination fosters antibody and T cell immune response independently from vaccine type used for the first two injections. However, such immune response is attenuated over time, suggesting thereby the need for further vaccinations.
Assuntos
COVID-19 , Vacinas Virais , Humanos , SARS-CoV-2 , Formação de Anticorpos , COVID-19/prevenção & controle , Vacinas de mRNARESUMO
BACKGROUND: Tumor cells modulate host immunity by secreting extracellular vesicles (EV) and soluble factors. Their interactions with myeloid cells lead to the generation of myeloid-derived suppressor cells (MDSC), which inhibit the antitumor function of T and NK cells. We demonstrated previously that EV derived from mouse and human melanoma cells induced immunosuppressive activity via increased expression of programmed cell death ligand 1 (PD-L1) on myeloid cells that was dependent on the heat-shock protein 90α (HSP90α) in EV. Here, we investigated whether soluble HSP90α could convert monocytes into MDSC. METHODS: CD14 monocytes were isolated from the peripheral blood of healthy donors, incubated with human recombinant HSP90α (rHSP90α) alone or in the presence of inhibitors of TLR4 signaling and analyzed by flow cytometry. Inhibition of T cell proliferation assay was applied to assess the immunosuppressive function of rHSP90α-treated monocytes. HSP90α levels were measured by ELISA in plasma of patients with advanced melanoma and correlated with clinical outcome. RESULTS: We found that the incubation of monocytes with rHSP90α resulted in a strong upregulation of PD-L1 expression, whereas reactive oxygen species (ROS) and nitric oxide (NO) production as well as the expression of arginase-1, ectoenzymes CD39 and CD73 remained unchanged. The PD-L1 upregulation was blocked by anti-TLR4 antibodies and a nuclear factor-κB inhibitor. rHSP90α-treated monocytes displayed the downregulation of HLA-DR expression and acquired the resistance to apoptosis. Moreover, these monocytes were converted into MDSC as indicated by their capacity to inhibit T cell proliferation, which was mediated by TLR4 signaling as well as PD-L1 and indoleamine 2,3-dioxygenase (IDO) 1 expression. Higher levels of HSP90α in plasma of patients with melanoma correlated with augmented PD-L1 expression on circulating monocytic (M)-MDSC. Patients with melanoma with high levels of HSP90α displayed shorter progression-free survival (PFS) on the treatment with immune checkpoint inhibitors (ICIs). CONCLUSION: Our findings demonstrated that soluble rHSP90α increased the resistance of normal human monocytes to apoptosis and converted them into immunosuppressive MDSC via TLR4 signaling that stimulated PD-L1 and IDO-1 expression. Furthermore, patients with melanoma with high concentrations of HSP90α displayed increased PD-L1 expression on M-MDSC and reduced PFS after ICI therapy, suggesting HSP90α as a promising therapeutic target for overcoming immunosuppression in melanoma.
Assuntos
Proteínas de Choque Térmico HSP90 , Melanoma , Células Supressoras Mieloides , Receptor 4 Toll-Like , Arginase/metabolismo , Antígeno B7-H1/metabolismo , Proteínas de Choque Térmico HSP90/farmacologia , Proteínas de Choque Térmico HSP90/uso terapêutico , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/uso terapêutico , Humanos , Inibidores de Checkpoint Imunológico , Imunossupressores/uso terapêutico , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Ligantes , Melanoma/tratamento farmacológico , Melanoma/patologia , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Receptor 4 Toll-Like/metabolismoRESUMO
BACKGROUND: Myeloid-derived suppressor cells (MDSCs) represent a negative prognostic factor in malignant melanoma. These cells are generated under chronic inflammatory conditions typical of cancer. The transcription factor signal transducer and activator of transcription 3 (STAT3) orchestrates MDSC accumulation and acquisition of immunosuppressive properties. Here we studied STAT3 inhibition by Napabucasin as a way to block MDSC accumulation and activity and its potential to treat malignant melanoma. METHODS: In vitro generated murine MDSC and primary MDSC from melanoma-bearing mice were used to investigate the effects of Napabucasin on MDSC in vitro. The RET transgenic mouse model of malignant melanoma was used to examine Napabucasin therapy efficiency and its underlying mechanisms in vivo. Furthermore, STAT3 activation and its correlation with survival were explored in MDSC from 19 patients with malignant melanoma and human in vitro generated monocytic myeloid-derived suppressor cell (M-MDSC) were used to evaluate the effects of Napabucasin. RESULTS: Napabucasin was able to abrogate the capacity of murine MDSC to suppress CD8+ T-cell proliferation. The STAT3 inhibitor induced apoptosis in murine MDSC, significantly increased expression of molecules associated with antigen processing and presentation, as well as slightly decreased expression of immunosuppressive factors on these cells. RET transgenic mice treated with Napabucasin showed prolonged survival accompanied by a strong accumulation of tumor-infiltrating antigen-presenting cells and activation of CD8+ and CD4+ T cells. Interestingly, patients with malignant melanoma with high expression of activated STAT3 in circulating M-MDSC showed significantly worse progression-free survival (PFS) than patients with low levels of activated STAT3. In addition, Napabucasin was able to abrogate suppressive capacity of human in vitro generated M-MDSC. CONCLUSION: Our findings demonstrate that STAT3 inhibitor Napabucasin completely abrogated the immunosuppressive capacity of murine MDSC and human M-MDSC and improved melanoma-bearing mouse survival. Moreover, patients with malignant melanoma with high expression levels of activated STAT3 in M-MDSC displayed shorter PFS, indicating its role as a promising therapeutic target in patients with malignant melanoma and a predictive marker for their clinical outcome.