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Immune checkpoint inhibitors (ICI) represent a breakthrough in cancer therapy. They are effective in various tumor entities and can be used in more and more treatment settings. This leads to an increase in the number and complexity of cases with immune-related adverse events (irAE). The most common irAE are cutaneous, gastrointestinal and endocrine side effects, whereas less common irAE include pneumonitis, nephritis, myocarditis or neurological reactions. IrAE can usually be successfully treated, mainly with corticosteroids or other immunosuppressants, but they can also result in long-term sequelae or death. The optimal management of patients with steroid-refractory or steroid-dependent side effects still remains unclear. Broad awareness of these irAE across specialties is therefore of crucial importance to ensure early diagnosis and to improve irAE management.
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BACKGROUND/AIM: The most frequently altered epigenetic modifier in head and neck squamous carcinoma (HNSC) is the histone methyltransferase KMT2D. KMT2D catalyzes methylation of histone H3K4 resulting in open chromatin and the activation of target genes. Tumor-associated macrophages (TAMs) promote cancer growth by causing T lymphocyte exhaustion. C-C motif chemokine ligand 2 (CCL2) is a potent TAM chemotactic factor. In HNSC, TAMs have been associated with unfavorable patient outcomes and metastasis. The aim of this study was to determine the role of KMT2D in HNSC using genetically engineered in vivo models. MATERIALS AND METHODS: KMT2D protein expression was correlated with lymph node metastasis in human HNSC using immunohistochemistry. Genetically engineered KMT2D and CCL2 knockout models of HNSC were created in vivo. HNSC was characterized using qRT-PCR, histopathology, and immunohistochemistry/immunofluorescence microscopy. We also analyzed the effects of KMT2D expression on the proliferation and migration of human HNSC lines. The regulation of the CCL2 gene by KMT2D was characterized using chromatin immunoprecipitation-sequencing assay of transposase accessible chromatin-sequencing, and chromatin conformation capture-sequencing. RESULTS: Human HNSC cases with high KMT2D expression exhibited significantly increased lymph node metastasis. Reduced KMT2D expression in our genetically engineered model correlated with reduced lymph node metastasis, longer latency, and slow tumor growth. CCL2 expression was decreased in KMT2D deficient HNSC, which correlated with a reduced TAM gene expression signature. Genomic experiments demonstrated that KMT2D directly targeted the CCL2 gene. A new genetically engineered in vivo model of CCL2-null HNSC was created, recapitulating the KMT2D deficient phenotype and showing a decreased T lymphocyte exhaustion signature. CONCLUSION: KMT2D regulates CCL2-mediated immune response and metastasis in HNSC.
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Quimiocina CCL2 , Neoplasias de Cabeza y Cuello , Humanos , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Animales , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Ratones , Línea Celular Tumoral , Metástasis Linfática , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/inmunología , Femenino , Movimiento CelularRESUMEN
Introduction: Our study investigated the potential of peripheral blood T cell CD25, CD28, and CTLA-4 gene transcription levels as predictive biomarkers for acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Real-time reverse transcription fluorescent quantitative PCR (RT-qPCR) analysis was conducted on day +7, +14, and +21 post-transplantation in patients undergoing allo-HSCT. Results: Elevated levels of CD25 and CTLA-4 mRNA were found to be associated with the occurrence of aGVHD, as well as severe and gastrointestinal aGVHD. Receiver operating characteristic (ROC) curve analysis was utilized to assess the predictive value of each biomarker. Combined analysis of CD25 and CTLA-4 mRNA levels demonstrated promising predictive potential for aGVHD. Conclusion: Our results confirmed that the transcription levels of CD25 and CTLA-4 genes could be used as early predictive biomarkers for aGVHD post-allo-HSCT.
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Biomarcadores , Antígeno CTLA-4 , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Subunidad alfa del Receptor de Interleucina-2 , Transcripción Genética , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/inmunología , Humanos , Antígeno CTLA-4/genética , Masculino , Subunidad alfa del Receptor de Interleucina-2/genética , Femenino , Adulto , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Persona de Mediana Edad , Enfermedad Aguda , Adulto Joven , Adolescente , Trasplante Homólogo/efectos adversos , PronósticoRESUMEN
Background: Tuberculosis (TB) persists as a global health challenge, with its treatment hampered by the side effects of long-term combination drug therapies and the growing issue of drug resistance. Therefore, the development of novel therapeutic strategies is critical. This study focuses on the role of immune checkpoint molecules (ICs) and functions of CD8+ T cells in the search for new potential targets against TB. Methods: We conducted differential expression genes analysis and CD8+ T cell functional gene analysis on 92 TB samples and 61 healthy individual (HI) samples from TB database GSE83456, which contains data on 34,603 genes. The GSE54992 dataset was used to validated the findings. Additionally, a cluster analysis on single-cell data from primates infected with mycobacterium tuberculosis and those vaccinated with BCG was performed. Results: The overexpression of LAG-3 gene was found as a potentially important characteristic of both pulmonary TB (PTB) and extrapulmonary TB (EPTB). Further correlation analysis showed that LAG-3 gene was correlated with GZMB, perforin, IL-2 and IL-12. A significant temporal and spatial variation in LAG-3 expression was observed in T cells and macrophages during TB infection and after BCG vaccination. Conclusion: LAG-3 was overexpressed in TB samples. Targeting LAG-3 may represent a potential therapeutic target for tuberculosis.
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Antígenos CD , Linfocitos T CD8-positivos , Proteína del Gen 3 de Activación de Linfocitos , Mycobacterium tuberculosis , Tuberculosis , Humanos , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/genética , Linfocitos T CD8-positivos/inmunología , Tuberculosis/inmunología , Tuberculosis/microbiología , Animales , Antígenos CD/genética , Vacuna BCG/inmunología , Macrófagos/inmunología , Macrófagos/microbiología , Interleucina-2/metabolismo , Interleucina-2/genética , Perfilación de la Expresión Génica , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiología , Interleucina-12/genética , Interleucina-12/metabolismo , Perforina/genética , Perforina/metabolismo , MasculinoRESUMEN
The transforming growth factor beta-activated kinase 1 (TAK1)/c-Jun N-terminal kinase (JNK) axis is an essential MAPK upstream mediator and regulates immune signaling pathways. However, whether the TAK1/JNK axis harnesses the strength in regulation of signal transduction in early vertebrate adaptive immunity is unclear. In this study, by modeling on Nile tilapia (Oreochromis niloticus), we investigated the potential regulatory function of TAK1/JNK axis on lymphocyte-mediated adaptive immune response. Both OnTAK1 and OnJNK exhibited highly conserved sequences and structures relative to their counterparts in other vertebrates. Their mRNA was widely expressed in the immune-associated tissues, while phosphorylation levels in splenic lymphocytes were significantly enhanced on the 4th day post-infection by Edwardsiella piscicida. In addition, OnTAK1 and OnJNK were significantly up-regulated in transcriptional level after activation of lymphocytes in vitro by phorbol 12-myristate 13-acetate plus ionomycin (P + I) or PHA, accompanied by a predominant increase in phosphorylation level. More importantly, inhibition of OnTAK1 activity by specific inhibitor NG25 led to a significant decrease in the phosphorylation level of OnJNK. Furthermore, blocking the activity of OnJNK with specific inhibitor SP600125 resulted in a marked reduction in the expression of T-cell activation markers including IFN-γ, CD122, IL-2, and CD44 during PHA-induced T-cell activation. In summary, these findings indicated that the conserved TAK1/JNK axis in Nile tilapia was involved in adaptive immune responses by regulating the activation of lymphocytes. This study enriched the current knowledge of adaptive immunity in teleost and provided a new perspective for understanding the regulatory mechanism of fish immunity.
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Inmunidad Adaptativa , Cíclidos , Enfermedades de los Peces , Proteínas de Peces , Activación de Linfocitos , Quinasas Quinasa Quinasa PAM , Animales , Cíclidos/inmunología , Cíclidos/genética , Proteínas de Peces/genética , Proteínas de Peces/inmunología , Enfermedades de los Peces/inmunología , Quinasas Quinasa Quinasa PAM/genética , Quinasas Quinasa Quinasa PAM/inmunología , Infecciones por Enterobacteriaceae/inmunología , Infecciones por Enterobacteriaceae/veterinaria , Edwardsiella/inmunología , Edwardsiella/fisiología , Regulación de la Expresión Génica/inmunología , Transducción de Señal/inmunología , Perfilación de la Expresión Génica/veterinaria , Filogenia , Alineación de Secuencia/veterinaria , Secuencia de AminoácidosRESUMEN
BACKGROUND: The pathogenesis of hypertension (HTN) in people living with HIV/AIDS (PLHIV) is complex and remains not fully understood. Chronic immune activation (IA) is postulated to be one of the culprits. This notion is derived from studies in HIV-uninfected populations and/or animals while data on HTN and how it relates to IA in PLHIV remains scarce. We determined the relationship between HTN and IA among antiretroviral therapy (ART) naïve PLHIV. METHODS: We analysed baseline data of 365 out of 430 clinical trial participants whose main aim was to investigate the effect of low-dose aspirin on HIV disease progression in PLHIV starting ART. Soluble CD14 (sCD14), T cells co-expressing CD38 and HLA-DR, and PD-1 were the IA and exhaustion markers, respectively studied and were analysed by flow cytometry. Mann-Whitney U-test was used for comparison of the markers by HTN status. A robust Poisson regression model was used to determine the predictors for HTN. RESULTS: A quarter of the 365 were hypertensive (25.3%, 95% CI 20.9-29.8%), and, had higher median (IQR) body mass index (kg/m2) (23.4 (19.6, 28.0) versus 21.9 (19.3, 25.1)) and lower median (IQR) estimated glomerular filtration rate (mL/min/1.73m2) (101.2 (79.4, 126.9) versus 113.6 (92.7, 138.8)) than normotensive participants (p < 0.05). Participants with HTN had higher median frequencies of all markers of IA and exhaustion but lower sCD14 (p > 0.05). None of these markers significantly predicted the occurrence of HTN. CONCLUSION: Studied markers of IA and exhaustion were higher in PLHIV with HTN than those without but were unpredictive of HTN. Larger multicentre studies with a wider range of markers are needed to confirm the role of IA in HIV-associated HTN.
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Infecciones por VIH , Hipertensión , Humanos , Masculino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/complicaciones , Femenino , Adulto , Hipertensión/tratamiento farmacológico , Hipertensión/inmunología , Persona de Mediana Edad , Receptores de Lipopolisacáridos/sangre , Biomarcadores/sangreRESUMEN
Lymphocyte phosphatase-associated phosphoprotein (LPAP) is a binding partner of the phosphatase CD45, but its function remains poorly understood. Its close interaction with CD45 suggests that LPAP may potentially regulate CD45, but direct biochemical evidence for this has not yet been obtained. We found that in the Jurkat lymphoid cells the levels of LPAP and CD45 proteins are interrelated and well correlated with each other. Knockout of LPAP leads to the decrease in the surface expression of CD45, while its overexpression, on the contrary, caused its increase. No such correlation was found in the non-lymphoid K562 cells. We hypothesize that LPAP regulates expression level of CD45 and thus can affect lymphocyte activation.
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Antígenos Comunes de Leucocito , Humanos , Antígenos Comunes de Leucocito/metabolismo , Células Jurkat , Células K562 , Estabilidad Proteica , Fosfoproteínas/metabolismo , Fosfoproteínas/genéticaRESUMEN
We report the generation of a novel anti-LAG-3/TIGIT bispecific IgG4 antibody, ZGGS15, and evaluated its anti-tumor efficacy in mouse models as monotherapy or in combination with a PD-1 antibody. ZGGS15 exhibited strong affinities for human LAG-3 and TIGIT, with KDs of 3.05 nM and 2.65 nM, respectively. ZGGS15 has EC50s of 0.69 nM and 1.87 nM for binding to human LAG-3 and TIGIT on CHO-K1 cells, respectively. ZGGS15 competitively inhibited the binding of LAG-3 to MHC-II (IC50 = 0.77 nM) and the binding of TIGIT to CD155 (IC50 = 0.24 nM). ZGGS15 does not induce ADCC, CDC, or obvious cytokine production. In vivo results showed that ZGGS15 had better anti-tumor inhibition than single anti-LAG-3 or anti-TIGIT agents and demonstrated a synergistic effect when combined with nivolumab, with a significantly higher tumor growth inhibition of 95.80% (p = 0.001). The tumor volume inhibition rate for ZGGS15 at 2 mg/kg was 69.70%, and for ZGGS15 at 5 mg/kg plus nivolumab at 1 mg/kg, it was 94.03% (p < 0.001). Our data reveal that ZGGS15 exhibits potent anti-tumor efficacy without eliciting ADCC or CDC or causing cytokine production, therefore having a safe profile.
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Anticuerpos Biespecíficos , Proteína del Gen 3 de Activación de Linfocitos , Receptor de Muerte Celular Programada 1 , Receptores Inmunológicos , Animales , Femenino , Humanos , Ratones , Anticuerpos Biespecíficos/farmacología , Anticuerpos Biespecíficos/uso terapéutico , Antígenos CD/inmunología , Antígenos CD/metabolismo , Línea Celular Tumoral , Células CHO , Cricetulus , Modelos Animales de Enfermedad , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: To investigate the effect of LAG-3 deficiency (LAG3-/-) on natural killer (NK) cell function and hepatic fibrosis in mice infected with Echinococcus multilocularis. METHODS: C57BL/6 mice, each weighing (20 ± 2) g, were divided into the LAG3-/- and wild type (WT) groups, and each mouse in both groups was inoculated with 3 000 E. multilocularis protoscoleces via the hepatic portal vein. Mouse liver and spleen specimens were collected 12 weeks post-infection, sectioned and stained with sirius red, and the hepatic lesions and fibrosis were observed. Mouse hepatic and splenic lymphocytes were isolated, and flow cytometry was performed to detect the proportions of hepatic and splenic NK cells, the expression of CD44, CD25 and CD69 molecules on NK cell surface, and the secretion of interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), interleukin (IL)-4, IL-10 and IL-17A. RESULTS: Sirius red staining showed widening of inflammatory cell bands and hyperplasia of fibrotic connective tissues around mouse hepatic lesions, as well as increased deposition of collagen fibers in the LAG3-/-group relative to the WT group. Flow cytometry revealed lower proportions of mouse hepatic (6.29% ± 1.06% vs. 11.91% ± 1.85%, P < 0.000 1) and splenic NK cells (4.44% ± 1.22% vs. 5.85% ± 1.10%, P > 0.05) in the LAG3-/- group than in the WT group, and the mean fluorescence intensity of CD44 was higher on the surface of mouse hepatic NK cells in the LAG3-/- group than in the WT group (t = -3.234, P < 0.01), while no significant differences were found in the mean fluorescence intensity of CD25 or CD69 on the surface of mouse hepaticNK cells between the LAG3-/- and WT groups (both P values > 0.05). There were significant differences between the LAG3-/- and WT groups in terms of the percentages of IFN-γ (t = -0.723, P > 0.05), TNF-α (t = -0.659, P > 0.05), IL-4 (t = -0.263, P > 0.05), IL-10 (t = -0.455, P > 0.05) or IL-17A secreted by mouse hepatic NK cells (t = 0.091, P > 0.05), and the percentage of IFN-γ secreted by mouse splenic NK cells was higher in the LAG3-/- group than in the WT group (58.40% ± 1.64% vs. 50.40% ± 4.13%; t = -4.042, P < 0.01); however, there were no significant differences between the two groups in terms of the proportions of TNF-α (t = -1.902, P > 0.05), IL-4 (t = -1.333, P > 0.05), IL-10 (t = -1.356, P > 0.05) or IL-17A secreted by mouse splenic NK cells (t = 0.529, P > 0.05). CONCLUSIONS: During the course of E. multilocularis infections, LAG3-/- promotes high-level secretion of IFN-γ by splenic NK cells, which may participate in the reversal the immune function of NK cells, resulting in aggravation of hepatic fibrosis.
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Echinococcus multilocularis , Interleucina-10 , Animales , Ratones , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Interleucina-17/farmacología , Interleucina-4/metabolismo , Interleucina-4/farmacología , Echinococcus multilocularis/genética , Factor de Necrosis Tumoral alfa/metabolismo , Ratones Endogámicos C57BL , Interferón gamma/genética , Interferón gamma/metabolismo , Células Asesinas Naturales/metabolismo , Cirrosis Hepática/genéticaRESUMEN
BACKGROUND: Ovarian cancer is the most lethal gynecological malignancy, with limited treatment options after failure of standard therapies. Despite the potential of poly(ADP-ribose) polymerase inhibitors in treating DNA damage response (DDR)-deficient ovarian cancer, the development of resistance and immunosuppression limit their efficacy, necessitating alternative therapeutic strategies. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) represent a novel class of inhibitors that are currently being assessed in preclinical and clinical studies for cancer treatment. METHODS: By using a PARG small-molecule inhibitor, COH34, and a cell-penetrating antibody targeting the PARG's catalytic domain, we investigated the effects of PARG inhibition on signal transducer and activator of transcription 3 (STAT3) in OVCAR8, PEO1, and Brca1-null ID8 ovarian cancer cell lines, as well as in immune cells. We examined PARG inhibition-induced effects on STAT3 phosphorylation, nuclear localization, target gene expression, and antitumor immune responses in vitro, in patient-derived tumor organoids, and in an immunocompetent Brca1-null ID8 ovarian mouse tumor model that mirrors DDR-deficient human high-grade serous ovarian cancer. We also tested the effects of overexpressing a constitutively activated STAT3 mutant on COH34-induced tumor cell growth inhibition. RESULTS: Our findings show that PARG inhibition downregulates STAT3 activity through dephosphorylation in ovarian cancer cells. Importantly, overexpression of a constitutively activated STAT3 mutant in tumor cells attenuates PARG inhibitor-induced growth inhibition. Additionally, PARG inhibition reduces STAT3 phosphorylation in immune cells, leading to the activation of antitumor immune responses, shown in immune cells cocultured with ovarian cancer patient tumor-derived organoids and in immune-competent mice-bearing mouse ovarian tumors. CONCLUSIONS: We have identified a novel antitumor mechanism underlying PARG inhibition beyond its primary antitumor effects through blocking DDR in ovarian cancer. Furthermore, targeting PARG activates antitumor immune responses, thereby potentially increasing response rates to immunotherapy in patients with ovarian cancer.
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Glicósido Hidrolasas , Neoplasias Ováricas , Factor de Transcripción STAT3 , Animales , Femenino , Humanos , Ratones , Línea Celular , Inmunidad , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Factor de Transcripción STAT3/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Glicósido Hidrolasas/antagonistas & inhibidores , Glicósido Hidrolasas/metabolismoRESUMEN
Psoriasis is a common chronic inflammatory skin disease characterized by abnormal activation and infiltration of T-cells and excessive proliferation of keratinocytes (KCs). Its pathogenesis is complex and frequently accompanied by the imbalance of T-cell subpopulations, contributing to its development and further exacerbation. Therefore, the immune system, especially T-cells, is mainly involved in the pathogenesis of psoriasis. While T-cell activation not only requires the first recognition of T-cell receptor and major histocompatibility complex peptide, co-stimulatory and co-inhibitory pathways are reported to promote or dampen T-cell responses through a variety of mechanisms. In recent years, immuno-related agents have been applied in the treatment of numerous clinical diseases, including psoriasis, and are starting to show promising and potential therapy prospects in autoimmune skin diseases. The present review outlined the role of co-inhibitory molecules in the pathogenesis of psoriasis and their application in the treatment of psoriasis.
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BACKGROUND: Checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway are effective therapies in a range of immunogenic cancer types. Blocking this pathway with an oral therapy could benefit patients through greater convenience, particularly in combination regimens, and allow flexible management of immune-mediated toxicities. METHODS: PD-L1 binding activity was assessed in engineered dimerization and primary cell target occupancy assays. Preclinical antitumor activity was evaluated in ex vivo and in vivo human PD-L1-expressing tumor models. Human safety, tolerability, pharmacokinetics, and biomarker activity were evaluated in an open-label, multicenter, sequential dose-escalation study in patients with advanced solid tumors. Biomarkers evaluated included target occupancy, flow cytometric immunophenotyping, plasma cytokine measurements, and T-cell receptor sequencing. RESULTS: GS-4224 binding caused dimerization of PD-L1, blocking its interaction with PD-1 and leading to reversal of T-cell inhibition and increased tumor killing in vitro and in vivo. The potency of GS-4224 was dependent on the density of cell surface PD-L1, with binding being most potent on PD-L1-high cells. In a phase 1 dose-escalation study in patients with advanced solid tumors, treatment was well tolerated at doses of 400-1,500 mg once daily. Administration of GS-4224 was associated with a dose-dependent increase in plasma GS-4224 exposure and reduction in free PD-L1 on peripheral blood T cells, an increase in Ki67 among the PD-1-positive T-cell subsets, and elevated plasma cytokines and chemokines. CONCLUSIONS: GS-4224 is a novel, orally bioavailable small molecule inhibitor of PD-L1. GS-4224 showed evidence of expected on-target biomarker activity, including engagement of PD-L1 and induction of immune-related pharmacodynamic responses consistent with PD-L1 blockade. TRIAL REGISTRATION NUMBER: NCT04049617.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Antígeno B7-H1 , Receptor de Muerte Celular Programada 1 , Neoplasias/tratamiento farmacológico , Linfocitos T/metabolismoRESUMEN
BACKGROUND: Despite the current therapeutic treatments including surgery, chemotherapy, radiotherapy and more recently immunotherapy, the mortality rate of lung cancer stays high. Regarding lung cancer, epigenetic modifications altering cell cycle, angiogenesis and programmed cancer cell death are therapeutic targets to combine with immunotherapy to improve treatment success. In a recent study, we uncovered that a molecule called QAPHA ((E)-3-(5-((2-cyanoquinolin-4-yl)(methyl)amino)-2-methoxyphenyl)-N-hydroxyacrylamide) has a dual function as both a tubulin polymerization and HDAC inhibitors. Here, we investigate the impact of this novel dual inhibitor on the immune response to lung cancer. METHODS: To elucidate the mechanism of action of QAPHA, we conducted a chemical proteomics analysis. Using an in vivo mouse model of lung cancer (TC-1 tumor cells), we assessed the effects of QAPHA on tumor regression. Tumor infiltrating immune cells were characterized by flow cytometry. RESULTS: In this study, we first showed that QAPHA effectively inhibited histone deacetylase 6, leading to upregulation of HSP90, cytochrome C and caspases, as revealed by proteomic analysis. We confirmed that QAPHA induces immunogenic cell death (ICD) by expressing calreticulin at cell surface in vitro and demonstrated its efficacy as a vaccine in vivo. Remarkably, even at a low concentration (0.5 mg/kg), QAPHA achieved complete tumor regression in approximately 60% of mice treated intratumorally, establishing a long-lasting anticancer immune response. Additionally, QAPHA treatment promoted the infiltration of M1-polarized macrophages in treated mice, indicating the induction of a pro-inflammatory environment within the tumor. Very interestingly, our findings also revealed that QAPHA upregulated major histocompatibility complex class II (MHC-II) expression on TC-1 tumor cells both in vitro and in vivo, facilitating the recruitment of cytotoxic CD4+T cells (CD4+CTL) expressing CD4+, NKG2D+, CRTAM+, and Perforin+. Finally, we showed that tumor regression strongly correlates to MHC-II expression level on tumor cell and CD4+ CTL infiltrate. CONCLUSION: Collectively, our findings shed light on the discovery of a new multitarget inhibitor able to induce ICD and MHC-II upregulation in TC-1 tumor cell. These two processes participate in enhancing a specific CD4+ cytotoxic T cell-mediated antitumor response in vivo in our model of lung cancer. This breakthrough suggests the potential of QAPHA as a promising agent for cancer treatment.
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Antineoplásicos , Neoplasias Pulmonares , Animales , Ratones , Neoplasias Pulmonares/tratamiento farmacológico , Proteómica , Regulación hacia Arriba , Antígenos de Histocompatibilidad Clase II , Linfocitos T CD4-PositivosRESUMEN
The spread of prion-like protein aggregates is a common driver of pathogenesis in various neurodegenerative diseases, including Alzheimer's disease (AD) and related Tauopathies. Tau pathologies exhibit a clear progressive spreading pattern that correlates with disease severity. Clinical observation combined with complementary experimental studies has shown that Tau preformed fibrils (PFF) are prion-like seeds that propagate pathology by entering cells and templating misfolding and aggregation of endogenous Tau. While several cell surface receptors of Tau are known, they are not specific to the fibrillar form of Tau. Moreover, the underlying cellular mechanisms of Tau PFF spreading remain poorly understood. Here, it is shown that the lymphocyte-activation gene 3 (Lag3) is a cell surface receptor that binds to PFF but not the monomer of Tau. Deletion of Lag3 or inhibition of Lag3 in primary cortical neurons significantly reduces the internalization of Tau PFF and subsequent Tau propagation and neuron-to-neuron transmission. Propagation of Tau pathology and behavioral deficits induced by injection of Tau PFF in the hippocampus and overlying cortex are attenuated in mice lacking Lag3 selectively in neurons. These results identify neuronal Lag3 as a receptor of pathologic Tau in the brainï¼and for AD and related Tauopathies, a therapeutic target.
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Proteína del Gen 3 de Activación de Linfocitos , Neuronas , Tauopatías , Proteínas tau , Animales , Humanos , Ratones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Antígenos CD/metabolismo , Antígenos CD/genética , Modelos Animales de Enfermedad , Neuronas/metabolismo , Proteínas tau/metabolismo , Proteínas tau/genética , Tauopatías/metabolismo , Tauopatías/genética , Tauopatías/patologíaRESUMEN
Immune checkpoints (ICs) play a central role in maintaining immune homoeostasis. The discovery that tumours use this physiological mechanism to avoid elimination by the immune system, opened up avenues for therapeutic targeting of ICs as a novel way of treating cancer. However, this therapy a new array of autoimmune side effects, termed immune-related adverse events (irAEs). In this narrative review, we first recapitulate the physiological function of ICs that are approved targets for cancer immunotherapy (CTLA-4, PD-(L)1 and LAG-3), as the groundwork to critically discuss current knowledge on irAEs. Specifically, we summarize clinical aspects and examine a molecular classification and predisposing factors of irAEs. Finally, we discuss irAE treatment, particularly emphasizing how molecular knowledge is changing the current treatment paradigm.
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Antineoplásicos Inmunológicos , Neoplasias , Humanos , Antineoplásicos Inmunológicos/uso terapéutico , Autoinmunidad , Neoplasias/patología , Inmunoterapia , BiologíaRESUMEN
In recent years, there have been notable advancements in the field of cancer immunotherapy, namely in the area of immune checkpoint inhibition. The Lymphocyte-activation gene 3 (LAG-3) has garnered attention as a potentially valuable focus of study in this particular field. The present study examines the biological aspects of LAG-3, its clinical consequences, and the potential therapeutic opportunities associated with its modulation. LAG-3, similar to CD4, has a regulatory role in modulating the immune system. The upregulation of this protein inside the neoplastic milieu hampers the immune system's ability to mount an effective response, hence enabling the evasion of cancer cells from immune surveillance. The LAG-3 protein interacts with ligands, inhibiting cytotoxic immune cells such as CD8+ T cells and NK cells. The potential of LAG-3 inhibitors presents intriguing prospects. Integrating these medicines with established treatments like PD-1/PD-L1 or CTLA-4 inhibitors can broaden the range of available therapy choices and address resistance issues. The advent of personalized therapy is imminent, as evidenced by the utilization of predictive biomarkers such as LAG-3 expression to inform individualized therapeutic approaches. Additionally, inhibitors of LAG-3 exhibit promise in addressing immunological depletion and resistance by revitalizing T cells and producing durable immune responses. The realization of LAG-3's promise necessitates global collaboration and equal access. Multinational trials are expected to ascertain the efficacy of the intervention in various patient groups.
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Antineoplásicos , Neoplasias , Humanos , Linfocitos T CD8-positivos/metabolismo , Inmunoterapia , Antineoplásicos/uso terapéutico , Biomarcadores , Biología , Neoplasias/tratamiento farmacológicoRESUMEN
Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition, and its diagnosis may be challenging. In particular, some cases show close similarities to sepsis (fever, organ failure, and high ferritin), but their treatment, while urgent, differ: prompt broad-spectrum antibiotherapy for sepsis and immunosuppressive treatment for HLH. We questioned whether monocyte human leucocyte antigen (mHLA)-DR could be a diagnostic marker for secondary HLH (sHLH). Methods: We retrospectively reviewed data from patients with a sHLH diagnosis and mHLA-DR quantification. mHLA-DR data from healthy children and children with septic shock, whose HLA-DR expression is reduced, from a previously published study were also included for comparison. Results: Six patients with sHLH had mHLA-DR quantification. The median level of monocyte mHLA-DR expression in patients with sHLH [79,409 antibodies bound per cell (AB/C), interquartile range (IQR) (75,734-86,453)] was significantly higher than that in healthy children and those with septic shock (29,668 AB/C, IQR (24,335-39,199), and 7,493 AB/C, IQR (3,758-14,659), respectively). Each patient with sHLH had a mHLA-DR higher than our laboratory normal values. Four patients had a second mHLA-DR sampling 2 to 4 days after the initial analysis and treatment initiation with high-dose corticosteroids; for all patients, mHLA-DR decreased to within or close to the normal range. One patient with systemic juvenile idiopathic arthritis had repeated mHLA-DR measurements over a 200-day period during which she underwent four HLH episodes. mHLA-DR increased during relapses and normalized after treatment incrementation. Conclusion: In this small series, mHLA-DR was systematically elevated in patients with sHLH. Elevated mHLA-DR could contribute to sHLH diagnosis and help earlier distinction with septic shock.
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Linfohistiocitosis Hemofagocítica , Sepsis , Choque Séptico , Femenino , Humanos , Niño , Estudios Retrospectivos , Monocitos , Linfohistiocitosis Hemofagocítica/diagnóstico , Antígenos HLA-DR , Sepsis/metabolismoRESUMEN
Whither oncolytic viruses? From the peak of their popularity in the early 2000s, when the ONYX-015 adenovirus had just entered the clinic, and then again in 2015 when the Food and Drug Administration-approved talimogene laherparepvec (also known as OncoVEXGM-CSF), which briefly revived interest, oncolytic viruses (OVs) have mostly fallen out of favor despite the many pharmaceutical companies with OVs in development.This commentary enumerates and addresses the core conceptions, perceptions, and misconceptions that characterize the current 'trough of disillusionment' in which the field of anticancer virotherapy finds itself and suggests reasons for optimism.
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Melanoma , Viroterapia Oncolítica , Virus Oncolíticos , Estados Unidos , Humanos , Virus Oncolíticos/genética , Melanoma/terapiaRESUMEN
Lymphocyte-activation gene 3 (LAG3) is a highly anticipated immune checkpoint in the context of cancer, exerting regulatory control over immune cell proliferation and function to reinforce the advancement of cancers. However, the comprehensive functional analysis of LAG3 across various cancer types remains undisclosed; thus, this study aims to investigate the pan-cancer expression profile of LAG3. We have investigated the expression profile, prognostic significance, and genetic alterations of LAG3 in various cancers while elucidating its characteristic in immune response regulation. Our findings demonstrated that elevated LAG3 expression is significantly associated with favorable prognosis in patients with cutaneous melanoma (SKCM), and it may be a potential biomarker for SKCM. Furthermore, multiple immune algorithms have highlighted the important regulatory role of LAG3 for the tumor-infiltrating immune cells including CD8 + T cells, B cells, dendritic cells (DCs), macrophages, and natural killer (NK) cells. We also examined the distribution of LAG3 at the single-cell level and explored its functional significance. A comprehensive and systematic analysis of LAG3 would facilitate a comprehensive evaluation of LAG3 in cancer biology and provide valuable insights for cancer management.
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Melanoma , Neoplasias Cutáneas , Humanos , Pronóstico , Antígenos CD/metabolismo , Melanoma/genética , Melanoma/terapia , Multiómica , Proteína del Gen 3 de Activación de Linfocitos , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/terapia , InmunoterapiaRESUMEN
When lymphocytes encounter their cognate antigen, they become activated and undergo a limited number of cell divisions during which they differentiate into memory or effector cells or die. While the dynamics of individual cells are often heterogeneous, the expansion kinetics at the population level are highly reproducible, suggesting a mean-field description. To generate a finite division destiny, we consider two scenarios: Cells stop dividing after a certain number of iterations or their death rate increases with each cell division. The dynamics of the combined system can be mapped to a partial differential equation, and for a suitable choice of the activation rate, we obtain simple analytical solutions for the total cell number and the mean number of divisions per cell which can well describe the signal-dependent T cell expansion kinetics from in vitro experiments. Interestingly, only the division cessation mechanism yields an expression for the division destiny that does not contradict experiments. We show that the generation-dependent decrease of the division rate in individual cells leads to a time-dependent decrease at the population level which is consistent with a "time-to-die" control mechanism for the division destiny as suggested previously. We also derive mean-field equations for the total cell number which provide a basis for implementing T cell expansion kinetics into quantitative systems pharmacology models for immuno-oncology and CAR-T cell therapies.