RESUMEN
BACKGROUND: Pyrimidine metabolism is critical for tumour progression. Uridine-cytidine kinase 2 (UCK2), a key regulator of pyrimidine metabolism, is elevated during hepatocellular carcinoma (HCC) development and exhibits carcinogenic effects. However, the key mechanism of UCK2 promoting HCC and the therapeutic value of UCK2 are still undefined. The aim of this study is to investigate the potential of UCK2 as a therapeutic target for HCC. METHODS: Gene expression matrices were obtained from public databases. RNA-seq, co-immunoprecipitation and RNA-binding protein immunoprecipitation were used to determine the mechanism of UCK2 promoting HCC. Immune cell infiltration level and immune-related functional scores were evaluated to assess the link between tumour microenvironment and UCK2. RESULTS: In HCC, the expression of UCK2 was upregulated in part by TGFß1 stimulation. UCK2 promoted cell cycle progression of HCC by preventing the degradation of mTOR protein and maintaining the stability of PDPK1 mRNA. We also identified UCK2 as a novel RNA-binding protein. Downregulation of UCK2 induced cell cycle arrest and activated the TNFα/NFκB signalling pathway-related senescence-associated secretory phenotype to modify the tumour microenvironment. Additionally, UCK2 was a biomarker of the immunosuppressive microenvironment. Downregulated UCK2 induced a secretory phenotype, which could improve the microenvironment, and decreased UCK2 remodelling metabolism could lower the resistance of tumour cells to T-cell-mediated killing. CONCLUSIONS: Targeting UCK2 inhibits HCC progression and could improve the response to immunotherapy in patients with HCC. Our study suggests that UCK2 could be an ideal target for HCC.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Uridina Quinasa , Humanos , Proteínas Quinasas Dependientes de 3-Fosfoinosítido , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/inmunología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/genética , Puntos de Control del Ciclo Celular/inmunología , Inmunidad/genética , Inmunidad/inmunología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inmunología , Pirimidinas , Microambiente Tumoral , Uridina Quinasa/genética , Uridina Quinasa/inmunologíaRESUMEN
Lymphostatin is a virulence factor of enteropathogenic E. coli (EPEC) and non-O157 serogroup enterohaemorrhagic E. coli. Previous studies using whole-cell lysates of EPEC showed that lymphostatin inhibits the mitogen-activated proliferation of bulk human peripheral blood mononuclear cells (PBMCs) and the production of cytokines IL-2, IL-4, IL-5, and IFN-γ. Here, we used highly purified lymphostatin and PBMC-derived T cells to show that lymphostatin inhibits anti-CD3/anti-CD28-activated proliferation of human CD4+ and CD8+ T cells and blocks the synthesis of IL-2, IL-4, IL-10 and IFN-γ without affecting cell viability and in a manner dependent on an N-terminal DTD glycosyltransferase motif. Such inhibition was not observed with T cells activated by phorbol 12-myristate 13-acetate and ionomycin, implying that lymphostatin targets T cell receptor signaling. Analysis of the expression of CD69 indicated that lymphostatin suppresses T cell activation at an early stage and no impacts on apoptosis or necrosis were observed. Flow cytometric analysis of the DNA content of lymphostatin-treated CD4+ and CD8+ T cells showed a concentration- and DTD-dependent accumulation of the cells in the G0/G1 phase of the cell cycle, and corresponding reduction of the percentage of cells in S phase. Consistent with this, we found a marked reduction in the abundance of cyclins D3, E and A and loss of phosphorylated Rb over time in activated T cells from 8 donors treated with lymphostatin. Moreover, the cyclin-dependent kinase (cdk) inhibitor p27kip1, which inhibits progression of the cell cycle at G1 by acting on cyclin E-cdk2 or cyclin D-cdk4 complexes, was found to be accumulated in lymphostatin-treated T cells. Analysis of the abundance of phosphorylated kinases involved in signal transduction found that 30 of 39 were reduced in abundance following lymphostatin treatment of T cells from 5 donors, albeit not significantly so. Our data provide novel insights into the mode of action of lymphostatin on human T lymphocytes.
Asunto(s)
Toxinas Bacterianas , Infecciones por Escherichia coli , Proteínas de Escherichia coli , Escherichia coli , Linfocitos T , Apoptosis , Toxinas Bacterianas/inmunología , Linfocitos T CD8-positivos/inmunología , Puntos de Control del Ciclo Celular/inmunología , División Celular , Proliferación Celular/fisiología , Citocinas/biosíntesis , Citocinas/inmunología , Escherichia coli Enteropatógena/inmunología , Escherichia coli Enteropatógena/patogenicidad , Escherichia coli/inmunología , Escherichia coli/patogenicidad , Infecciones por Escherichia coli/inmunología , Proteínas de Escherichia coli/inmunología , Humanos , Interleucina-2 , Interleucina-4 , Leucocitos Mononucleares/inmunología , Necrosis , Linfocitos T/inmunología , Factores de Virulencia/inmunologíaRESUMEN
CD19 CAR T-cell immunotherapy is a breakthrough treatment for B cell malignancies, but relapse and lack of response remain a challenge. The bone marrow microenvironment is a key factor in therapy resistance, however, little research has been reported concerning the relationship between transcriptomic profile of bone marrow prior to lymphodepleting preconditioning and clinical response following CD19 CAR T-cell therapy. Here, we applied comprehensive bioinformatic methods (PCA, GO, GSEA, GSVA, PAM-tools) to identify clinical CD19 CAR T-cell remission-related genomic signatures. In patients achieving a complete response (CR) transcriptomic profiles of bone marrow prior to lymphodepletion showed genes mainly involved in T cell activation. The bone marrow of CR patients also showed a higher activity in early T cell function, chemokine, and interleukin signaling pathways. However, non-responding patients showed higher activity in cell cycle checkpoint pathways. In addition, a 14-gene signature was identified as a remission-marker. Our study indicated the indexes of the bone marrow microenvironment have a close relationship with clinical remission. Enhancing T cell activation pathways (chemokine, interleukin, etc.) in the bone marrow before CAR T-cell infusion may create a pro-inflammatory environment which improves the efficacy of CAR T-cell therapy.
Asunto(s)
Antígenos CD19/inmunología , Células de la Médula Ósea/inmunología , Inmunoterapia Adoptiva , Leucemia Linfocítica Crónica de Células B/terapia , Adulto , Antígenos CD19/genética , Antígenos CD19/uso terapéutico , Linfocitos B/inmunología , Linfocitos B/fisiología , Trasplante de Médula Ósea , Puntos de Control del Ciclo Celular/genética , Puntos de Control del Ciclo Celular/inmunología , Femenino , Humanos , Inmunoterapia/métodos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/terapia , Linfocitos T/inmunología , Linfocitos T/trasplante , Transcriptoma/genética , Resultado del Tratamiento , Microambiente Tumoral/inmunologíaRESUMEN
BACKGROUND: Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report. CASE: We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy. DISCUSSION: Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma. CONCLUSION: ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.
Asunto(s)
Adenoma Hipofisario Secretor de ACTH/tratamiento farmacológico , Adenoma/tratamiento farmacológico , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/tratamiento farmacológico , Adenoma Hipofisario Secretor de ACTH/inmunología , Adenoma/inmunología , Adulto , Carcinoma/inmunología , Puntos de Control del Ciclo Celular/inmunología , Humanos , Ipilimumab/uso terapéutico , Masculino , Nivolumab/uso terapéuticoRESUMEN
Romidepsin (FK228), a histone deacetylase inhibitor (HDACi), has anti-tumor effects against several types of solid tumors. Studies have suggested that HDACi could upregulate PD-L1 expression in tumor cells and change the state of anti-tumor immune responses in vivo. However, the influence of enhanced PD-L1 expression in tumor cells induced by romidepsin on anti-tumor immune responses is still under debate. So, the purpose of this study was to explore the anti-tumor effects and influence on immune responses of romidepsin in colon cancer. The results indicated that romidepsin inhibited proliferation, induced G0/G1 cell cycle arrest and increased apoptosis in CT26 and MC38 cells. Romidepsin treatment increased PD-L1 expression in vivo and in vitro via increasing the acetylation levels of histones H3 and H4 and regulating the transcription factor BRD4. In subcutaneous transplant tumor mice and colitis-associated cancer (CAC) mice, romidepsin increased the percentage of FOXP3+ regulatory T cells (Tregs), decreased the ratio of Th1/Th2 cells and the percentage of IFN-γ+ CD8+ T cells in the peripheral blood and the tumor microenvironment. Upon combination with an anti-PD-1 antibody, the anti-tumor effects of romidepsin were enhanced and the influence on CD4+ and CD8+ T cells was partially reversed. Therefore, the combination of romidepsin and anti-PD-1 immunotherapy provides a more potential treatment for colon cancer.
Asunto(s)
Antígeno B7-H1/antagonistas & inhibidores , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/inmunología , Depsipéptidos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inmunidad Celular/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/inmunología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/metabolismo , Femenino , Fase G1/efectos de los fármacos , Fase G1/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Histonas/metabolismo , Inmunoterapia/métodos , Ligandos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Fase de Descanso del Ciclo Celular/efectos de los fármacos , Fase de Descanso del Ciclo Celular/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Factores de Transcripción/metabolismo , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
Merkel cell carcinoma (MCC) is a rare, highly aggressive skin cancer for which immune modulation by immune checkpoint inhibitors shows remarkable response rates. However, primary or secondary resistance to immunotherapy prevents benefits in a significant proportion of patients. For MCC, one immune escape mechanism is insufficient for recognition by T cells owing to the downregulation of major histocompatibility complex I surface expression. Histone deacetylase inhibitors have been demonstrated to epigenetically reverse the low major histocompatibility complex I expression caused by the downregulation of the antigen-processing machinery. Domatinostat, an orally available small-molecule inhibitor targeting histone deacetylase class I, is currently in clinical evaluation to overcome resistance to immunotherapy. In this study, we present preclinical data on domatinostat's efficacy and mode of action in MCC. Single-cell RNA sequencing revealed a distinct gene expression signature of antigen processing and presentation, cell-cycle arrest, and execution phase of apoptosis on treatment. Accordingly, functional assays showed that domatinostat induced G2M arrest and apoptosis. In the surviving cells, antigen-processing machinery component gene transcription and translation were upregulated, consequently resulting in increased major histocompatibility complex I surface expression. Altogether, domatinostat not only exerts direct antitumoral effects but also restores HLA class I surface expression on MCC cells, therefore, restoring surviving MCC cells' susceptibility to recognition and elimination by cognate cytotoxic T cells.
Asunto(s)
Benzamidas/farmacología , Carcinoma de Células de Merkel/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Neoplasias Cutáneas/tratamiento farmacológico , Presentación de Antígeno/genética , Apoptosis/efectos de los fármacos , Apoptosis/genética , Apoptosis/inmunología , Benzamidas/uso terapéutico , Carcinoma de Células de Merkel/genética , Carcinoma de Células de Merkel/inmunología , Carcinoma de Células de Merkel/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/genética , Puntos de Control del Ciclo Celular/inmunología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Regulación Neoplásica de la Expresión Génica/inmunología , Antígenos de Histocompatibilidad Clase I/genética , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , RNA-Seq , Análisis de la Célula Individual , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Linfocitos T Citotóxicos/inmunología , Escape del Tumor/efectos de los fármacos , Escape del Tumor/genéticaRESUMEN
Human natural killer cell deficiency (NKD) arises from inborn errors of immunity that lead to impaired NK cell development, function, or both. Through the understanding of the biological perturbations in individuals with NKD, requirements for the generation of terminally mature functional innate effector cells can be elucidated. Here, we report a cause of NKD resulting from compound heterozygous mutations in minichromosomal maintenance complex member 10 (MCM10) that impaired NK cell maturation in a child with fatal susceptibility to CMV. MCM10 has not been previously associated with monogenic disease and plays a critical role in the activation and function of the eukaryotic DNA replisome. Through evaluation of patient primary fibroblasts, modeling patient mutations in fibroblast cell lines, and MCM10 knockdown in human NK cell lines, we have shown that loss of MCM10 function leads to impaired cell cycle progression and induction of DNA damage-response pathways. By modeling MCM10 deficiency in primary NK cell precursors, including patient-derived induced pluripotent stem cells, we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function. Together, these data define MCM10 as an NKD gene and provide biological insight into the requirement for the DNA replisome in human NK cell maturation and function.
Asunto(s)
Células Asesinas Naturales/inmunología , Proteínas de Mantenimiento de Minicromosoma/genética , Mutación , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/inmunología , Alelos , Puntos de Control del Ciclo Celular/genética , Puntos de Control del Ciclo Celular/inmunología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Línea Celular , Codón sin Sentido , Daño del ADN/genética , Daño del ADN/inmunología , Resultado Fatal , Femenino , Técnicas de Silenciamiento del Gen , Heterocigoto , Humanos , Células Madre Pluripotentes Inducidas/inmunología , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/patología , Lactante , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/patología , Masculino , Proteínas de Mantenimiento de Minicromosoma/metabolismo , Modelos Inmunológicos , Mutación Missense , Linaje , Enfermedades de Inmunodeficiencia Primaria/patologíaRESUMEN
PURPOSE OF REVIEW: To summarize a new form of autoimmune diabetes as an adverse event of specific cancer immunotherapies. Immune checkpoint inhibitors are revolutionary treatments in advanced cancers; however, they can cause type 1 diabetes following treatment with these state-of-the-art therapies. RECENT FINDINGS: A review of the literature showed that this new form of autoimmune diabetes has significant similarities with childhood-onset type 1 diabetes but also some distinctions. It frequently presents with severe diabetic ketoacidosis and almost half of the patients have type 1 diabetes-associated antibodies at presentation. Rapid loss of residual beta-cell function with a lack of honeymoon phase is typical. Certain human leukocyte antigen risk genes for prototypical type 1 diabetes that develops in children and young adults are also commonly found in patients with immune checkpoint inhibitor-induced type 1 diabetes. SUMMARY: Immune checkpoint inhibitor-induced type 1 diabetes presenting with diabetic ketoacidosis is a life-threatening adverse event of cancer immunotherapy. Healthcare providers should be aware of this adverse event to prevent morbidity and mortality related to diabetic ketoacidosis. Developing guidelines to identify and monitor risk groups are of utmost importance.
Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Diabetes Mellitus Tipo 1/etiología , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Adolescente , Adulto , Anticuerpos Monoclonales/uso terapéutico , Puntos de Control del Ciclo Celular/inmunología , Niño , Diabetes Mellitus Tipo 1/inmunología , Cetoacidosis Diabética/etiología , Cetoacidosis Diabética/inmunología , Humanos , Inmunoterapia/efectos adversos , Neoplasias/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND: Modulated electro-hyperthermia (mEHT) is a form of hyperthermia used in cancer treatment. mEHT has demonstrated the ability to activate host immunity by inducing the release of heat shock proteins, triggering apoptosis, and destroying the integrity of cell membranes to enhance cellular uptake of chemo-drugs in tumor cells. Both curcumin and resveratrol are phytochemicals that function as effective antioxidants, immune activators, and potential inhibitors of tumor development. However, poor bioavailability is a major obstacle for use in clinical cancer treatment. METHODS: This purpose of this study was to investigate whether mEHT can increase anti-cancer efficacy of nanosized curcumin and resveratrol in in vitro and in vivo models. The in vitro study included cell proliferation assay, cell cycle, and apoptosis analysis. Serum concentration was analyzed for the absorption of curcumin and resveratrol in SD rat model. The in vivo CT26/BALB/c animal tumor model was used for validating the safety, tumor growth curve, and immune cell infiltration within tumor tissues after combined mEHT/curcumin/resveratrol treatment. RESULTS: The results indicate co-treatment of mEHT with nano-curcumin and resveratrol significantly induced cell cycle arrest and apoptosis of CT26 cells. The serum concentrations of curcumin and resveratrol were significantly elevated when mEHT was applied. The combination also inhibited the growth of CT26 colon cancer by inducing apoptosis and HSP70 expression of tumor cells while recruiting CD3+ T-cells and F4/80+ macrophages. CONCLUSIONS: The results of this study have suggested that this natural, non-toxic compound can be an effective anti-tumor strategy for clinical cancer therapy. mEHT can enable cellular uptake of potential anti-tumor materials and create a favorable tumor microenvironment for an immunological chain reaction that improves the success of combined treatments of curcumin and resveratrol.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias Colorrectales/terapia , Curcumina/administración & dosificación , Terapia por Estimulación Eléctrica/métodos , Hipertermia Inducida/métodos , Resveratrol/administración & dosificación , Animales , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/farmacocinética , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Disponibilidad Biológica , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/inmunología , Línea Celular Tumoral/trasplante , Neoplasias Colorrectales/patología , Terapia Combinada/métodos , Curcumina/efectos adversos , Curcumina/farmacocinética , Modelos Animales de Enfermedad , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Masculino , Ratones , Nanopartículas/administración & dosificación , Ratas , Resveratrol/efectos adversos , Resveratrol/farmacocinética , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
Serum interleukin-8 (IL-8) levels and tumor neutrophil infiltration are associated with worse prognosis in advanced cancers. Here, using a large-scale retrospective analysis, we show that elevated baseline serum IL-8 levels are associated with poor outcome in patients (n = 1,344) with advanced cancers treated with nivolumab and/or ipilimumab, everolimus or docetaxel in phase 3 clinical trials, revealing the importance of assessing serum IL-8 levels in identifying unfavorable tumor immunobiology and as an independent biomarker in patients receiving immune-checkpoint inhibitors.
Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Biomarcadores Farmacológicos/sangre , Interleucina-8/sangre , Neoplasias/tratamiento farmacológico , Neutrófilos/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Biomarcadores de Tumor/sangre , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/inmunología , Estudios de Cohortes , Femenino , Humanos , Masculino , Neoplasias/sangre , Neoplasias/diagnóstico , Neoplasias/mortalidad , Infiltración Neutrófila/efectos de los fármacos , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Insuficiencia del Tratamiento , Microambiente Tumoral/inmunología , Regulación hacia ArribaRESUMEN
Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy1-3. However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found5 despite the frequent downregulation of MHC-I expression6-8. Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8+ T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.
Asunto(s)
Adenocarcinoma/inmunología , Autofagia/inmunología , Carcinoma Ductal Pancreático/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Neoplasias Pancreáticas/inmunología , Escape del Tumor/inmunología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patología , Animales , Presentación de Antígeno/efectos de los fármacos , Presentación de Antígeno/inmunología , Autofagia/efectos de los fármacos , Autofagia/genética , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/inmunología , Línea Celular Tumoral , Cloroquina/farmacología , Femenino , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Masculino , Ratones , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Escape del Tumor/efectos de los fármacosRESUMEN
The ready availability of human blood makes it the first choice for immuno-monitoring. However, this has been largely confined to static metrics, particularly resting T cell phenotypes. Conversely, dynamic assessments have mostly relied on cell stimulation in vitro which is subject to multiple variables. Here, immunodynamic insights from the peripheral blood are shown to be obtainable by applying a revised approach to cell-cycle analysis. Specifically, refined flow cytometric protocols were employed, assuring the reliable quantification of T cells in the S-G2/M phases of the cell-cycle (collectively termed "T Double S" for T cells in S-phase in Sanguine: in short "TDS" cells). Without protocol refinement, TDS could be either missed, as most of them layed out of the conventional lymphocyte gates, or confused with cell doublets artefactually displaying high DNA-content. To illustrate the nature of TDS cells, and their relationship to different immunodynamic scenarios, we examined them in healthy donors (HD); infectious mononucleosis (IM) patients versus asymptomatic EBV+ carriers; and recently-diagnosed T1D patients. TDS were reproducibly more abundant among CD8+ T cells and a defined subset of T-regulatory CD4+ T cells, and were substantially increased in IM and a subset of T1D patients. Of note, islet antigen-reactive TDS cell frequencies were associated with an aggressive T cell effector phenotype, suggesting that peripheral blood can reflect immune events within tissues in T1D, and possibly in other organ-specific autoimmune diseases. Our results suggest that tracking TDS cells may provide a widely applicable means of gaining insight into ongoing immune response dynamics in a variety of settings, including tissue immunopathologies where the peripheral blood has often not been considered insightful.
Asunto(s)
Puntos de Control del Ciclo Celular/inmunología , Monitorización Inmunológica/métodos , Linfocitos T/inmunología , Animales , Citometría de Flujo/métodos , Humanos , Ratones , Ratones TransgénicosRESUMEN
Cancer immunotherapy, especially immune checkpoint blockade therapy, represents a hotspot in cancer research. However, the low response rate, adaptive/acquired resistance, and adverse effects still keep most cancer patients from obtaining sustained clinical benefits. To overcome these limitations, it is essential to improve our understanding on the regulation of immune checkpoints under physiological and pathological contexts. Recent researches have gained insights into the molecular control of immune checkpoint receptors and ligands, which extended our knowledge on the immune system and provided alternative strategies for developing checkpoint inhibitors.
Asunto(s)
Inmunoterapia/tendencias , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/inmunología , Humanos , Inmunoterapia/efectos adversos , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/inmunologíaRESUMEN
The first generation of immune checkpoint inhibitors (ICIs) including anti-CTLA-4 and anti-PD-1/anti-PD-L1 has achieved profound and great success. Till 2019 Q1, there are nine ICIs landing the oncology market: Ipilimumab (anti-CTLA-4, Bristol-Myers Squibb), Nivolumab (anti-PD-1, Bristol-Myers Squibb), Pembrolizumab (anti-PD-1, Merck), Atezolizumab (anti-PD-L1, Roche/Genentech), Durvalumab (anti-PD-L1, Astra Zeneca), Tremelimumab (anti-CTLA-4, Astra Zeneca), Cemiplimab (anti-PD-1, Sanofi/Regeneron), Toripalimab (anti-PD-1, Junshi), and Sintilimab (anti-PD-1, Innovent), which have covered the majority of hematologic and solid malignancies' indication. Beyond the considerable benefits for the patients, frustrated boundary still exists: limited response rate in monotherapy in late-stage population, poor effectiveness in neoplasms with immune desert and immune excluded types, and immune-related toxicities, some are life-threatened and with higher incidence in I-O combination regiment. Moreover, clinicians observed some cases switching to progression after achieving partial or complete response, indicating treatment failure or drug resistance. So people begin looking for the next generation of immune checkpoint members.
Asunto(s)
Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/inmunología , Descubrimiento de Drogas , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Receptores Inmunológicos/antagonistas & inhibidores , Humanos , Neoplasias/patologíaRESUMEN
Immune checkpoint blockade (ICB) therapy has become a promising way of overcoming cancers, whereas the therapy can induce immunopathology due to the disruption of the immune homeostasis. These adverse events caused by ICB are named as immune-related adverse events (irAEs), which can be severe and life-threaten. Understanding the mechanisms and managements of irAEs is critical for improving the efficacy of immune checkpoint therapy. Immune-related adverse events can occur on various organs, and gastrointestinal tract has the highest rate for severe irAEs. Accumulated evidences indicate the ability of the gut microbiota in regulating the response to immune checkpoint therapy, but the function of microbiota in irAEs remains unclear. T cells, including functional subsets: Th17 T cells and regulatory T (Treg) cells, play significant roles in determining the inflammatory microenvironment. The gut immune tolerance toward dietary antigens and commensals, and anti-inflammatory function in intestines are maintained mainly by Treg cells. Furthermore, tissue residency of functional T cells depends on the homing/trafficking to the locations of inflammation. Here, we review the role of microbiota and the interaction between microbiota and intestinal Treg cells in irAEs, and discuss the function of gut-trafficking blockade antibodies in the context of ICB therapy.
Asunto(s)
Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/inmunología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Neoplasias/tratamiento farmacológico , Receptores Inmunológicos/antagonistas & inhibidores , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/inmunología , Microbioma Gastrointestinal/fisiología , Humanos , Intestinos/efectos de los fármacos , Intestinos/inmunología , Neoplasias/patología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
Immunotherapy with checkpoint inhibitor has been successfully applied in treatment for multiple cancer types, especially for patients at advanced stage. However, response rate of this promising therapy is low, thus requiring biomarkers for precise medication to reduce the ineffective treatment. With multiple retrospective clinical studies, more and more candidate prognostic factors have been identified with possible mechanic explanation, including the basic clinical characteristics (e.g., age and gender), molecular features (e.g., PD-L1 expression and tumor mutation burden). After validation in independent patient cohorts with large sample size, several markers have been approved as companion biomarkers. However, validation and combinations of all the possible candidate biomarkers are still challenging to predict the treatment outcomes. In this chapter, we will summarize and introduce the prognostic factors and biomarkers for checkpoint inhibitor-based immunotherapy.
Asunto(s)
Biomarcadores de Tumor/análisis , Inmunoterapia , Neoplasias/tratamiento farmacológico , Receptores Inmunológicos/antagonistas & inhibidores , Antígeno B7-H1/antagonistas & inhibidores , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/inmunología , Humanos , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/patología , Pronóstico , Reproducibilidad de los Resultados , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Immune checkpoint molecules, including inhibitory and stimulatory immune checkpoint molecules, are defined as ligand-receptor pairs that exert inhibitory or stimulatory effects on immune responses. Most of the immune checkpoint molecules that have been described so far are expressed on cells of the adaptive immune system, particularly on T cells, and of the innate immune system. They are crucial for maintaining the self-tolerance and modulating the length and magnitude of immune responses of effectors in different tissues to minimize the tissue damage. More and more evidences have shown that inhibitory or stimulatory immune checkpoint molecules are expressed on a sizeable fraction of tumor types. Although the main function of tumor cell-associated immune checkpoint molecules is considered to mediate the immune evasion, it has been reported that the immune checkpoint molecules expressed on tumor cells also play important roles in the maintenance of many malignant behaviors, including self-renewal, epithelial-mesenchymal transition, metastasis, drug resistance, anti-apoptosis, angiogenesis, or enhanced energy metabolisms. In this section, we mainly focus on delineating the roles of the tumor cell-associated immune checkpoint molecules beyond immune evasion, such as PD-L1, PD-1, B7-H3, B7-H4, LILRB1, LILRB2, TIM3, CD47, CD137, and CD70.
Asunto(s)
Puntos de Control del Ciclo Celular/inmunología , Evasión Inmune , Tolerancia Inmunológica , Neoplasias/inmunología , Neoplasias/metabolismo , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Transición Epitelial-Mesenquimal , Humanos , Evasión Inmune/inmunología , Tolerancia Inmunológica/inmunología , Linfocitos T/inmunologíaRESUMEN
Somatic cells of an organism virtually share the same DNA but it is the timely expression of specific genes that determine their phenotype and cellular identity. A series of complex molecular machinery allows for the regulated process of RNA transcription, splicing, and translation. In addition, microRNAs and specialized RNA binding proteins can trigger the degradation of mRNAs. Long non-coding RNAs can also regulate mRNA fate in multiple ways. In this chapter, we reviewed the RNA processing mechanisms directly regulating immune checkpoint genes. We also cover RNA-based therapeutic strategies aiming at restoring immunity by targeting immune checkpoint genes.
Asunto(s)
Regulación de la Expresión Génica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Animales , Puntos de Control del Ciclo Celular/genética , Puntos de Control del Ciclo Celular/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Empalme del ARN , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Mensajero/uso terapéutico , Proteínas de Unión al ARN/metabolismoRESUMEN
In this chapter, we will sketch a story that begins with the breakdown of chromosome homeostasis and genomic stability. Genomic alterations may render tumor cells eternal life at the expense of immunogenicity. Although antitumor immunity can be primed through neoantigens or inflammatory signals, tumor cells have evolved countermeasures to evade immune surveillance and strike back by modulating immune checkpoint related pathways. At present, monoclonal antibody drugs targeting checkpoints like PD-1 and CTLA-4 have significantly prolonged the survival of a variety of cancer patients, and thus have marked a great achievement in the history of antitumor therapy. Nevertheless, this is not the end of the story. As the relationship between genomic alteration and checkpoint expression is being delineated though the advances of preclinical animal models and emerging technologies, novel checkpoint targets are on the way to be discovered.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/genética , Descubrimiento de Drogas , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Animales , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Puntos de Control del Ciclo Celular/inmunología , Humanos , Neoplasias/inmunología , Neoplasias/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismoRESUMEN
In consistent with other membrane-bound and secretory proteins, immune checkpoint proteins go through a set of modifications in the endoplasmic reticulum (ER) to acquire their native functional structures before they function at their destinations. There are various ER-resident chaperones and enzymes synergistically regulate and catalyze the glycosylation, folding and transporting of proteins. The whole processing is under the surveillance of ER quality control system which allows the correctly folded proteins to exit from the ER with the help of coat proteinII(COPII) coated vesicles, while retains the rest of terminally misfolded ones in the ER and then eliminates them via ER-associated degradation (ERAD) or ER-to-lysosomes-associated degradation (ERLAD). The dysfunction of the ER causes ER stress which triggers unfolded protein response (UPR) to restore ER proteostasis. Unsolvable prolonged ER stress ultimately results in cell death. This chapter reviews the process that proteins undergo in the ER, and the glycosylation, folding and degradation of immune checkpoint proteins as well as the associated potential immunotherapies to date.