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1.
Immunology ; 159(1): 75-87, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31587253

RESUMEN

Dendritic cell (DC) -based cancer immunotherapy is one of the most important anti-cancer immunotherapies, and has been associated with variable efficiencies in different cancer types. It is well-known that tumor microenvironment plays a key role in the efficacy of various immunotherapies such as DC vaccine. Accordingly, the expression of programmed death ligand 1 (PD-L1) on DCs, which interacts with PD-1 on T cells, leads to inhibition of anti-tumor responses following presentation of tumor antigens by DCs to T cells. Therefore, we hypothesized that down-regulation of PD-L1 in DCs in association with silencing of PD-1 on T cells may lead to the enhancement of T-cell priming by DCs to have efficient anti-tumor T-cell responses. In this study, we silenced the expression of PD-L1 in DCs and programmed cell death protein 1 (PD-1) in T cells by small interfering RNA (siRNA) -loaded chitosan-dextran sulfate nanoparticles (NPs) and evaluated the DC phenotypic and functional characteristics and T-cell functions following tumor antigen recognition on DCs, ex vivo. Our results showed that synthesized NPs had good physicochemical characteristics (size 77·5 nm and zeta potential of 14·3) that were associated with efficient cellular uptake and target gene silencing. Moreover, PD-L1 silencing was associated with stimulatory characteristics of DCs. On the other hand, presentation of tumor antigens by PD-L1-negative DCs to PD-1-silenced T cells led to induction of potent T-cell responses. Our findings imply that PD-L1-silenced DCs can be considered as a potent immunotherapeutic approach in combination with PD-1-siRNA loaded NPs, however; further in vivo investigation is required in animal models.


Asunto(s)
Antígeno B7-H1/inmunología , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/inmunología , Neoplasias del Colon/terapia , Células Dendríticas/trasplante , Activación de Linfocitos , Linfocitos Infiltrantes de Tumor/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Tratamiento con ARN de Interferencia , Linfocitos T/inmunología , Animales , Apoptosis , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Movimiento Celular , Técnicas de Cocultivo , Neoplasias del Colon/genética , Neoplasias del Colon/inmunología , Neoplasias del Colon/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Femenino , Linfocitos Infiltrantes de Tumor/metabolismo , Ratones Endogámicos BALB C , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Transducción de Señal , Linfocitos T/metabolismo
2.
Immunity ; 51(6): 1043-1058.e4, 2019 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-31810882

RESUMEN

T cell dysfunction is a characteristic feature of chronic viral infection and cancer. Recent studies in chronic lymphocytic choriomeningitis virus (LCMV) infection have defined a PD-1+ Tcf-1+ CD8+ T cell subset capable of self-renewal and differentiation into more terminally differentiated cells that downregulate Tcf-1 and express additional inhibitory molecules such as Tim3. Here, we demonstrated that expression of the glycoprotein CD101 divides this terminally differentiated population into two subsets. Stem-like Tcf-1+ CD8+ T cells initially differentiated into a transitory population of CD101-Tim3+ cells that later converted into CD101+ Tim3+ cells. Recently generated CD101-Tim3+ cells proliferated in vivo, contributed to viral control, and were marked by an effector-like transcriptional signature including expression of the chemokine receptor CX3CR1, pro-inflammatory cytokines, and granzyme B. PD-1 pathway blockade increased the numbers of CD101-Tim3+ CD8+ T cells, suggesting that these newly generated transitional cells play a critical role in PD-1-based immunotherapy.


Asunto(s)
Antígenos CD/metabolismo , Linfocitos T CD8-positivos/inmunología , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Animales , Biomarcadores/metabolismo , Receptor 1 de Quimiocinas CX3C/genética , Receptor 1 de Quimiocinas CX3C/metabolismo , Femenino , Granzimas/genética , Granzimas/metabolismo , Receptor 2 Celular del Virus de la Hepatitis A/biosíntesis , Factor Nuclear 1-alfa del Hepatocito/genética , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Coriomeningitis Linfocítica/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Receptor de Muerte Celular Programada 1/genética
3.
Nat Med ; 25(11): 1715-1720, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31700181

RESUMEN

Functional diversity of the highly polymorphic human leukocyte antigen class I (HLA-I) genes underlies successful immunologic control of both infectious disease and cancer. The divergent allele advantage hypothesis dictates that an HLA-I genotype with two alleles with sequences that are more divergent enables presentation of more diverse immunopeptidomes1-3. However, the effect of sequence divergence between HLA-I alleles-a quantifiable measure of HLA-I evolution-on the efficacy of immune checkpoint inhibitor (ICI) treatment for cancer remains unknown. In the present study the germline HLA-I evolutionary divergence (HED) of patients with cancer treated with ICIs was determined by quantifying the physiochemical sequence divergence between HLA-I alleles of each patient's genotype. HED was a strong determinant of survival after treatment with ICIs. Even among patients fully heterozygous at HLA-I, patients with an HED in the upper quartile respond better to ICIs than patients with a low HED. Furthermore, HED strongly impacts the diversity of tumor, viral and self-immunopeptidomes and intratumoral T cell receptor clonality. Similar to tumor mutation burden, HED is a fundamental metric of diversity at the major histocompatibility complex-peptide complex, which dictates ICI efficacy. The data link divergent HLA allele advantage to immunotherapy efficacy and unveil how ICI response relies on the evolved efficiency of HLA-mediated immunity.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/terapia , Evolución Molecular , Genes MHC Clase I/genética , Variación Genética/genética , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos/genética , Femenino , Genes MHC Clase I/inmunología , Predisposición Genética a la Enfermedad , Variación Genética/inmunología , Genotipo , Humanos , Inmunoterapia/efectos adversos , Masculino , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética
4.
Zhonghua Xue Ye Xue Za Zhi ; 40(9): 759-763, 2019 Sep 14.
Artículo en Chino | MEDLINE | ID: mdl-31648479

RESUMEN

Objective: To observe the changes of PD-1 expression, mRNA level and cytotoxic activity of CD19 CAR-T cells during the culture process of CAR-T cells. Methods: The peripheral blood T cells of 6 lymphoma patients with high expression of PD-1 and 6 healthy volunteers were the source of CAR-T cells. The expression of PD-1 was analyzed by flow cytometry. The mRNA level of PD-1 was analyzed by PCR. The cell proliferation was analyzed by CCK-8 assay. The cytotoxicity was analyzed by LDH assay. Results: ①The transfection efficiency of high PD-1 expression T cells and healthy volunteer T cells were as the same (P>0.05) . ②The cell proliferation capacity of CD19 CAR-T cells from high PD-1 expression T cells or healthy volunteer T cells, with or without PD-1 inhibitor were as the same (P>0.05) . ③The cytotoxicity to lymphoma cells of high PD-1 expression T cells and CAR-T cells were lower than that of these two T cells combined with PD-1 inhibitor and the CAR-T cells from healthy volunteer T cells (P<0.001) . There was no difference of the cytotoxicity between the CAR-T cells from high PD-1 expression T cells combined with PD-1 inhibitor and the CAR-T cells from healthy volunteer (P>0.05) . ④There was no difference of the expression of PD-1 in all CAR-T cell groups during the culture process (P>0.05) . There was no difference of mRNA level of PD-1 in all groups during the culture process (P>0.05) . ⑤The PD-1 expression of CAR-T cells increased by the time of culture after contacting with lymphoma cells (P<0.001) . The PD-1 inhibitors could antagonize this effect. There was no difference of mRNA level of PD-1 in all groups after contacting with lymphoma cells (P>0.05) . Conclusion: The PD-1 expression of CAR-T cells from high PD-1 expression T cells increased by the time of culture after contacting with lymphoma cells. However, the mRNA level of PD-1 of all groups did not change, even if PD-1 inhibitor was applied.


Asunto(s)
Receptor de Muerte Celular Programada 1/genética , Linfocitos T , Antígenos CD19 , Humanos , ARN Mensajero , Receptores de Antígenos de Linfocitos T
5.
Adv Exp Med Biol ; 1164: 225-233, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31576552

RESUMEN

Immune checkpoint blockade (ICB) has proved successful in the immunotherapeutic treatment of various human cancers. Despite its success, most patients are still not cured while immunogenic cold cancers are still poorly responsive. There is a need for novel clinical interventions in immunotherapy, either alone or in conjunction with ICB. Here, we outline our recent discovery that the intracellular signaling kinase glycogen synthase kinase-3 (GSK-3) is a central regulator of PD-1 in T-cells. We demonstrate the application of small molecule inhibitor (SMI) approaches to down-regulate PD-1 in tumor immunotherapy. GSK-3 SMIs were found as effective as anti-PD-1 in the elimination of melanoma in mouse models. We propose the development of novel SMIs to target co-receptors for the future of immunotherapy.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Glucógeno Sintasa Quinasa 3 , Inmunoterapia , Melanoma , Animales , Modelos Animales de Enfermedad , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Humanos , Melanoma/terapia , Ratones , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T/fisiología
6.
Plant Sci ; 288: 110242, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31521226

RESUMEN

Abscission is a developmental process that leads to shedding of organs not needed by the plant. Apart from wall hydrolysis, the cells of the abscission zone (AZ) are also believed to undergo programmed cell death (PCD). We show that ethylene-induced petal abscission in Rosa bourboniana is accompanied with the activation of RbPCD1 (PROGRAMMED CELL DEATH LIKE 1) encoding a protein of 78 amino acids. Its expression increases during natural and ethylene-induced petal abscission. Its transcription in most tissues is up-regulated by ethylene. RbPCD1 shows similarity to the N-terminal domain of animal PDCD4 (PROGRAMMED CELL DEATH PROTEIN 4) proteins that are activated during apoptosis and function as transcriptional and translational repressors. RbPCD1 resides in the nucleus and cytoplasm and acts as a transcriptional repressor. Constitutive expression of RbPCD1 in transgenic Arabidopsis is seedling lethal. Heat-induced expression of RbPCD1 under the soybean heat-shock promoter affects leaf function, inflorescence development, silique formation, seed yield and reduces survival. Nuclear localization of RbPCD1 is necessary for manifestation of its effects. RbPCD1 may be necessary to mediate some of the ethylene-induced changes during abscission and senescence in specific tissues.


Asunto(s)
Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas/genética , Receptor de Muerte Celular Programada 1/genética , Rosa/genética , Factores de Transcripción/genética , Secuencia de Aminoácidos , Arabidopsis/genética , Arabidopsis/crecimiento & desarrollo , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Plantas Modificadas Genéticamente/genética , Plantas Modificadas Genéticamente/crecimiento & desarrollo , Receptor de Muerte Celular Programada 1/química , Receptor de Muerte Celular Programada 1/metabolismo , Rosa/crecimiento & desarrollo , Alineación de Secuencia , Factores de Transcripción/química , Factores de Transcripción/metabolismo
7.
Nat Commun ; 10(1): 4415, 2019 09 27.
Artículo en Inglés | MEDLINE | ID: mdl-31562329

RESUMEN

Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell tolerance and concomitant autoantibody production. CD8+ Tfh cells share similar gene signatures with CD4+ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-cell tolerance.


Asunto(s)
Linfocitos B/inmunología , Linfocitos T CD8-positivos/inmunología , Tolerancia Inmunológica/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Receptores CXCR5/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Autoanticuerpos/inmunología , Autoanticuerpos/metabolismo , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Linfocitos B/metabolismo , Antígenos CD40/genética , Antígenos CD40/inmunología , Antígenos CD40/metabolismo , Ligando de CD40/genética , Ligando de CD40/inmunología , Ligando de CD40/metabolismo , Linfocitos T CD8-positivos/metabolismo , Perfilación de la Expresión Génica/métodos , Humanos , Tolerancia Inmunológica/genética , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Receptores CXCR5/genética , Receptores CXCR5/metabolismo , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/inmunología , Factor de Transcripción STAT5/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismo
8.
Magy Onkol ; 63(3): 239-245, 2019 09 18.
Artículo en Húngaro | MEDLINE | ID: mdl-31538441

RESUMEN

Skin cancers represent the most common type of malignancy. The incidence rate of melanoma and non-melanoma skin cancer depicts a continuous rise worldwide, which is attributed mainly (but not exclusively) to the growing incidence of non-melanoma skin cancer in the elderly population. Most skin cancer types are sensitive to immunotherapy. Melanoma, Merkel cell carcinoma, cutaneous squamous cell carcinoma showed response rates of at least 40% for PD-1 inhibitor therapy as reported in recent articles. In this article we review the current and future immunotherapy agents and procedures for skin cancers.


Asunto(s)
Inmunoterapia/mortalidad , Inmunoterapia/métodos , Receptor de Muerte Celular Programada 1/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Carcinoma de Células de Merkel/inmunología , Carcinoma de Células de Merkel/patología , Carcinoma de Células de Merkel/terapia , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Supervivencia sin Enfermedad , Femenino , Humanos , Hungría , Masculino , Melanoma/inmunología , Melanoma/patología , Melanoma/terapia , Terapia Molecular Dirigida/métodos , Pronóstico , Medición de Riesgo , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Análisis de Supervivencia , Resultado del Tratamiento
9.
Immunology ; 158(2): 136-149, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31515801

RESUMEN

Immune-checkpoint blockade antibodies have been approved for the treatment of cancer. However, poorly immunogenic tumours are less responsive to such therapies. Agonistic anti-Toll-like receptor 4 (TLR4) monoclonal antibodies (mAbs) activate only cell-surface TLR4; in contrast, lipopolysaccharide (LPS) activates both TLR4 and intracellular inflammatory caspases. In this study, we investigated the adjuvant activity of an anti-TLR4 mAb in T-cell-mediated antitumour immunity. The anti-TLR4 mAb induced the activation of antigen-specific T-cells in adoptive transfer studies. The growth of ovalbumin (OVA)-expressing tumours was significantly suppressed by administration of OVA and the anti-TLR4 mAb in combination, but not individually. The antitumour effect of anti-PD-1 mAb was enhanced in mice administered with OVA plus the anti-TLR4 mAb. The OVA-specific IFN-γ-producing CD8 T-cells were induced by administration of OVA and the anti-TLR4 mAb. The suppression of tumour growth was diminished by depletion of CD8, but not CD4, T-cells. The inflammatory response to the anti-TLR4 mAb was of significantly lesser magnitude than that to LPS, as assessed by NF-κB activation and production of TNF-α, IL-6 and IL-1ß. Administration of LPS (at a dose that elicited levels of proinflammatory cytokines comparable to those by the anti-TLR4 mAb) plus OVA induced no or less-marked activation of OVA-specific T-cells and failed to suppress tumour growth in mice. In conclusion, the agonistic anti-TLR4 mAb induces potent CD8 T-cell-dependent antitumour immunity and an inflammatory response of lesser magnitude than does LPS. The agonistic anti-TLR4 mAb has potential as an adjuvant for use in vaccines against cancer.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Anticuerpos Monoclonales/farmacología , Antineoplásicos Inmunológicos/farmacología , Melanoma Experimental/terapia , Neoplasias Cutáneas/terapia , Receptor Toll-Like 4/antagonistas & inhibidores , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Inmunización , Inmunoterapia/métodos , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Lipopolisacáridos/farmacología , Activación de Linfocitos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Melanoma Experimental/genética , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , FN-kappa B/genética , FN-kappa B/inmunología , Ovalbúmina/administración & dosificación , Cultivo Primario de Células , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/patología , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología
10.
Medicine (Baltimore) ; 98(33): e16773, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31415379

RESUMEN

Conventional therapy modalities for advanced breast cancer are problematic, whereas checkpoint blockade immunotherapy has been considered as a promising approach. This study aims to determine programmed death-ligand 1 (PD-L1) expression and methylation status of PD-L1 promoter in primary tumor tissue and metastatic foci of patients with stage IV breast cancer.Clinicopathological data and survival rates of 57 breast cancer patients, who were initially staged IV, and operated for intact tumors, were retrospectively analyzed. Immunohistochemical analysis of PD-L1 using 57 primary tumors, 33 paired metastatic lymph nodes, and 14 paired distant metastases was performed. Additionally, the methylation rate of the PD-L1 gene promoter region was determined with real-time polymerase chain reaction (PCR) analysis in 38 samples.Overall PD-L1 expression in primary tumors was 23.1% (12/52). PD-L1 positivity was reduced in lymph nodes by 15.2% (5/33) and in distant metastases by 21.4% (3/14). PD-L1 expression diverged between primary and metastatic foci in a subset of cases (18.2% for lymph node and 33.3% for distant metastasis). In general, the PD-L1 promoter was not methylated, and mean methylation rates were low (min. 0%-max. 21%). We observed no correlation between PD-L1 expression, promoter methylation, and survival.Neither the expression nor the methylation status of PD-L1 in patients, who were presented with stage IV breast cancer and operated for an intact primary tumor, had a statistically significant relation with survival. Discordance in PD-L1 expression between primary tumor and metastasis should be considered during pathological and clinical management of patients who would undergo checkpoint blockade therapy.


Asunto(s)
Antígeno B7-H1/metabolismo , Neoplasias de la Mama/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Antígeno B7-H1/genética , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Metilación , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Receptor de Muerte Celular Programada 1/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Turquia
11.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-31370215

RESUMEN

Dedifferentiated endometrial carcinoma (DDEC) is defined as an undifferentiated carcinoma admixed with differentiated endometrioid carcinoma (Grade 1 or 2). It has poor prognosis compared with Grade 3 endometrioid adenocarcinoma and is often associated with the loss of mismatch repair (MMR) proteins, which is seen in microsatellite instability (MSI)-type endometrial cancer. Recent studies have shown that the effectiveness of immune checkpoint inhibitor therapy is related to MMR deficiency; therefore, we analyzed the immunophenotype (MMR deficient and expression of PD-L1) of 17 DDEC cases. In the undifferentiated component, nine cases (53%) were deficient in MMR proteins and nine cases (53%) expressed PD-L1. PD-L1 expression was significantly associated with MMR deficiency (p = 0.026). In addition, the presence of tumor-infiltrating lymphocytes (CD8+) was significantly associated with MMR deficiency (p = 0.026). In contrast, none of the cases showed PD-L1 expression in the well-differentiated component. Our results show that DDEC could be a target for immune checkpoint inhibitors (anti PD-L1/PD-1 antibodies), especially in the undifferentiated component. As a treatment strategy for DDEC, conventional paclitaxel plus carboplatin and cisplatin plus doxorubicin therapies are effective for those with the well-differentiated component. However, by using immune checkpoint inhibitors in combination with other conventional treatments, it may be possible to control the undifferentiated component and improve prognosis.


Asunto(s)
Anticuerpos Neutralizantes/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Endometrioide/tratamiento farmacológico , Carcinoma/tratamiento farmacológico , Neoplasias Endometriales/tratamiento farmacológico , Anciano , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Carboplatino/uso terapéutico , Carcinoma/genética , Carcinoma/inmunología , Carcinoma/patología , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/inmunología , Carcinoma Endometrioide/patología , Cisplatino/uso terapéutico , Reparación de la Incompatibilidad de ADN/efectos de los fármacos , Doxorrubicina/uso terapéutico , Neoplasias Endometriales/genética , Neoplasias Endometriales/inmunología , Neoplasias Endometriales/patología , Femenino , Expresión Génica , Humanos , Inmunofenotipificación , Linfocitos Infiltrantes de Tumor , Inestabilidad de Microsatélites , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/uso terapéutico , Pronóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología
12.
Immunology ; 158(1): 35-46, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31429085

RESUMEN

Chronic inflammation may drive development of cancer as observed in inflammation-induced colorectal cancer (CRC). Though immune cells can infiltrate the tumour microenvironment, cancer cells seem to evade anti-tumour responses, which is one of the established hallmarks of cancer. Targeting the programmed cell death protein-1 (PD-1)/PD-L1 signalling pathway is currently at the forefront in the development of anti-tumour immunity-based therapies for multiple malignancies. By blocking the immune-checkpoint of activated T-cells, it is possible to rewire the adaptive resistance induced by the PD-1 ligands expressed in the tumour microenvironment. However, adverse immunotherapy-modulated events could complicate the treatment of individuals with preexisting chronic inflammatory conditions. In this study, we investigated the expression of different systemic and mucosal T-cell subsets during the course of azoxymethane (AOM)/dextran sulphate sodium (DSS)-induced colitis and colitis-associated CRC. In addition, we examined the expression of PD-1 and its ligands PD-L1 and PD-L2 as well as other molecular targets related to T-cell exhaustion. We found a significant increase in PD-1 expression on all examined mucosal T-cell subsets of the colon and the ileum, which correlated with disease progression. We also observed an upregulation of PD-L1 and PD-L2 mRNA expression throughout the AOM/DSS regime. Blocking PD-1 signalling with an anti-PD1 antibody did not affect the tumour burden in the AOM/DSS-treated mice, but did potentiate the weight loss in the third DSS cycle, indicating possible immune-mediated toxicity. This raises a concern for patients with colitis-associated CRCs and should be further investigated.


Asunto(s)
Azoximetano , Colitis/metabolismo , Colon/metabolismo , Neoplasias Colorrectales/metabolismo , Sulfato de Dextran , Mucosa Intestinal/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T/metabolismo , Animales , Antígeno B7-H1/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/inmunología , Transformación Celular Neoplásica/metabolismo , Colitis/inducido químicamente , Colitis/genética , Colitis/inmunología , Colon/inmunología , Neoplasias Colorrectales/inducido químicamente , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Mucosa Intestinal/inmunología , Activación de Linfocitos , Ratones Endogámicos C57BL , Fenotipo , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/genética , Transducción de Señal , Linfocitos T/inmunología , Regulación hacia Arriba
13.
Zhongguo Fei Ai Za Zhi ; 22(8): 541-545, 2019 Aug 20.
Artículo en Chino | MEDLINE | ID: mdl-31451147

RESUMEN

Targeted therapy and immunotherapy are important treatments for non-small cell lung cancer (NSCLC). At present, the clinical and basic research of epidermal growth factor receptor (EGFR) mutation NSCLC is still in the exploratory stage, needing to optimize the efficacy, combination, sequence and dosage of immunotherapy and other treatments, to clarify the relationship between EGFR mutation, immune microenvironment and the efficacy of immunotherapy. In this review, we summarized the newly updated data about immunotherapy in EGFR mutant NSCLC in term of pre-clinical study, programmed cell death protein ligand 1 (PD-L1) expression, tumor mutation burden and treatment.
.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/terapia , Receptores ErbB/genética , Inmunoterapia , Neoplasias Pulmonares/terapia , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mutación , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo
14.
JAMA ; 322(8): 764-774, 2019 08 27.
Artículo en Inglés | MEDLINE | ID: mdl-31454018

RESUMEN

Importance: Non-small cell lung cancer remains the leading cause of cancer death in the United States. Until the last decade, the 5-year overall survival rate for patients with metastatic non-small cell lung cancer was less than 5%. Improved understanding of the biology of lung cancer has resulted in the development of new biomarker-targeted therapies and led to improvements in overall survival for patients with advanced or metastatic disease. Observations: Systemic therapy for metastatic non-small cell lung cancer is selected according to the presence of specific biomarkers. Therefore, all patients with metastatic non-small cell lung cancer should undergo molecular testing for relevant mutations and expression of the protein PD-L1 (programmed death ligand 1). Molecular alterations that predict response to treatment (eg, EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutations) are present in approximately 30% of patients with non-small cell lung cancer. Targeted therapy for these alterations improves progression-free survival compared with cytotoxic chemotherapy. For example, somatic activating mutations in the EGFR gene are present in approximately 20% of patients with advanced non-small cell lung cancer. Tyrosine kinase inhibitors such as gefitinib, erlotinib, and afatinib improve progression-free survival in patients with susceptible EGFR mutations. In patients with overexpression of ALK protein, the response rate was significantly better with crizotinib (a tyrosine kinase inhibitor) than with the combination of pemetrexed and either cisplatin or carboplatin (platinum-based chemotherapy) (74% vs 45%, respectively; P < .001) and progression-free survival (median, 10.9 months vs 7.0 months; P < .001). Subsequent generations of tyrosine kinase inhibitors have improved these agents. For patients without biomarkers indicating susceptibility to specific targeted treatments, immune checkpoint inhibitor-containing regimens either as monotherapy or in combination with chemotherapy are superior vs chemotherapy alone. These advances in biomarker-directed therapy have led to improvements in overall survival. For example, the 5-year overall survival rate currently exceeds 25% among patients whose tumors have high PD-L1 expression (tumor proportion score of ≥50%) and 40% among patients with ALK-positive tumors. Conclusions and Relevance: Improved understanding of the biology and molecular subtypes of non-small cell lung cancer have led to more biomarker-directed therapies for patients with metastatic disease. These biomarker-directed therapies and newer empirical treatment regimens have improved overall survival for patients with metastatic non-small cell lung cancer.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Terapia Molecular Dirigida , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/análisis , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/secundario , Puntos de Control del Ciclo Celular , Genes erbB-1 , Humanos , Inmunoterapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética , Supervivencia sin Progresión , Tasa de Supervivencia
15.
Medicine (Baltimore) ; 98(35): e16972, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31464942

RESUMEN

Single nuclear polymorphism (SNP) of programmed cell death 1 (PD-1) was reported associated with hepatitis B virus (HBV) infection, but the SNP sites studied were limited. Whether the combination of 2 or more SNP sites could better represent the relationship between PD-1 SNP and HBV infection was not studied.Eight hundred ninety-eight HBV-infected patients (222 asymptomatic carriers [AsC], 276 chronic hepatitis B, 105 acute-on-chronic liver failure, and 295 liver cirrhosis) and 364 health controls of South China were enrolled in this study. Four PD-1 SNPs (rs10204525, rs2227982, rs41386349, and rs36084323) were selected and detected by TaqMan probe. The frequency of allele, genotype, and combination of different SNPs were compared between different groups.For allele frequency analysis, G allele of rs10204525 was protective factor (odds ratio (OR) = 0.823, 95% confidence interval (CI) = 0.679-0.997, P = .046) and T allele of rs2227982 was predisposing factor (OR = 1.231, 95% CI = 1.036-1.463, P = .018) in HBV infection. When analyzed in genotype frequency, the genotype GG of rs10204525 and CC of rs2227982 were protective factor of HBV infection. Combination of rs10204525 GG and rs2227982 CC was potent protective factor of HBV infection (OR = 0.552, 95% CI = 0.356-0.857, P = .007) and was also associated with lower HBV load (OR = 0.201, 95% CI = 0.056-0.728, P = .008) in AsC. The 4 SNP sites were not associated with progression of HBV-related liver disease.Rs10204525 and rs2227982 of PD-1 associate with HBV infection and combination of the 2 SNP sites can better predict host susceptibility in HBV infection.


Asunto(s)
Hepatitis B/genética , Receptor de Muerte Celular Programada 1/genética , Factores de Edad , Alelos , Estudios de Casos y Controles , China/epidemiología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Pruebas de Función Hepática , Masculino , Polimorfismo de Nucleótido Simple , Estudios Retrospectivos , Factores Sexuales
16.
Anticancer Res ; 39(8): 4539-4548, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31366557

RESUMEN

BACKGROUND/AIM: The aim of this study was to investigate PD-L1 expression and its association with prognosis in esophageal squamous cell carcinoma (ESCC) before and after neoadjuvant chemotherapy (5-fluorouracil and cisplatin, NAC-FP). PATIENTS AND METHODS: Using a database of 69 ESCC patients, we analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs), as well as the density of CD8+ tumor-infiltrating lymphocytes (TILs) in pretreatment biopsy specimens-versus-surgical specimens after resection. We determined the prognostic significance of these factors. RESULTS: The fraction of ESCC containing ICs expressing PD-L1 and having a high CD8+ TIL density was significantly increased after neoadjuvant treatment. However, PD-L1 expression on TCs or ICs, and CD8+ TIL density, was not significantly associated with patient survival in ESCC patients. CONCLUSION: NAC-FP induced PD-L1 expression on ICs and CD8+ TILs in ESCC patients. This finding suggests that PD-1/PD-L1 blockade could be combined with NAC-FP to treat ESCC patients.


Asunto(s)
Antígeno B7-H1/genética , Biomarcadores de Tumor/sangre , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/genética , Anciano , Antígeno B7-H1/sangre , Linfocitos T CD8-positivos/efectos de los fármacos , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Carcinoma de Células Escamosas de Esófago/sangre , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Fluorouracilo/administración & dosificación , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Estimación de Kaplan-Meier , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Pronóstico , Receptor de Muerte Celular Programada 1/sangre , Microambiente Tumoral/efectos de los fármacos
17.
Med Oncol ; 36(9): 76, 2019 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-31342270

RESUMEN

The microenvironment of a tumor may regulate the anti-tumor immune response. Intratumoral acidosis and hypoxia may suppress lymphocyte proliferation and migration, and this may have important implications in modern immunotherapy. The expression of PD-L1 by cancer cells and of PD-1 by tumor infiltrating lymphocytes (TILs) was assessed in tissue specimens from 98 operable NSCLC patients. Their prognostic role and their association with makers of glycolysis and anaerobic metabolism were assessed. Strong cytoplasmic/membrane PD-L1 expression was noted in 45/98 cases. Intense presence of TILs was noted in 42/98 cases (high TIL-score), and intense presence of PD-1 expressing TILs (high PIL-score) in 17/98 cases. PD-L1 expression was directly correlated with high PIL-score (p = 0.005). A significant inverse relationship was found between lactate dehydrogenase LDH5 expression and PIL-score (p = 0.008). Similarly, low PIL-score was significantly linked with high-hexokinase HXKII and monocarboxylate transporter MCT2 expression (p < 0.04). Cases with both intense TIL-score and PIL-score had significantly better survival (p < 0.05). For patients with high TIL-score or high PIL-score, PD-L1 overexpression defined significantly poorer survival (p = 0.01 and p = 0.03, respectively). In multivariate analysis, stage (p = 0.002, HR 3.33, 95%CI 1.4-4.5) and TIL-score (p = 0.02, HR 2.12, 95%CI 1.1-4.0) were independent predictive variables of death events. Given the low specificity of PD-L1 as a biomarker for anti-PD-1/PD-L1 immunotherapy, a combined assessment of TIL, PD-L1, PD-1, and LDH5 provides a tool for an immunological/metabolic classification of NSCLC tumors, with a different prognosis and different expected response to anti-PD-1/PD-L1 immunotherapy, which should be considered in relevant clinical trials.


Asunto(s)
Antígeno B7-H1/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Glucólisis/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Receptor de Muerte Celular Programada 1/genética , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Glucólisis/genética , Hexoquinasa/metabolismo , Humanos , Neoplasias Pulmonares/patología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Masculino , Persona de Mediana Edad , Transportadores de Ácidos Monocarboxílicos/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Análisis de Supervivencia , Microambiente Tumoral
18.
Nat Commun ; 10(1): 3345, 2019 07 26.
Artículo en Inglés | MEDLINE | ID: mdl-31350404

RESUMEN

Neuropilin-1 (Nrp-1) is a marker for murine CD4+FoxP3+ regulatory T (Treg) cells, a subset of human CD4+ Treg cells, and a population of CD8+ T cells infiltrating certain solid tumours. However, whether Nrp-1 regulates tumour-specific CD8 T-cell responses is still unclear. Here we show that Nrp-1 defines a subset of CD8+ T cells displaying PD-1hi status and infiltrating human lung cancer. Interaction of Nrp-1 with its ligand semaphorin-3A inhibits migration and tumour-specific lytic function of cytotoxic T lymphocytes. In vivo, Nrp-1+PD-1hi CD8+ tumour-infiltrating lymphocytes (TIL) in B16F10 melanoma are enriched for tumour-reactive T cells exhibiting an exhausted state, expressing Tim-3, LAG-3 and CTLA-4 inhibitory receptors. Anti-Nrp-1 neutralising antibodies enhance the migration and cytotoxicity of Nrp-1+PD-1hi CD8+ TIL ex vivo, while in vivo immunotherapeutic blockade of Nrp-1 synergises with anti-PD-1 to enhance CD8+ T-cell proliferation, cytotoxicity and tumour control. Thus, Nrp-1 could be a target for developing combined immunotherapies.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Inmunoterapia , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Neuropilina-1/inmunología , Animales , Movimiento Celular , Femenino , Humanos , Inmunidad Celular , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/fisiopatología , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Ratones Endogámicos C57BL , Neuropilina-1/genética , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Semaforina-3A/inmunología , Linfocitos T Citotóxicos/citología , Linfocitos T Citotóxicos/inmunología
19.
Nat Neurosci ; 22(8): 1289-1305, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31285612

RESUMEN

The effects of autonomic innervation of tumors on tumor growth remain unclear. Here we developed a series of genetic techniques to manipulate autonomic innervation in a tumor- and fiber-type-specific manner in mice with human breast cancer xenografts and in rats with chemically induced breast tumors. Breast cancer growth and progression were accelerated following stimulation of sympathetic nerves in tumors, but were reduced following stimulation of parasympathetic nerves. Tumor-specific sympathetic denervation suppressed tumor growth and downregulated the expression of immune checkpoint molecules (programed death-1 (PD-1), programed death ligand-1 (PD-L1), and FOXP3) to a greater extent than with pharmacological α- or ß-adrenergic receptor blockers. Genetically induced simulation of parasympathetic innervation of tumors decreased PD-1 and PD-L1 expression. In humans, a retrospective analysis of breast cancer specimens from 29 patients revealed that increased sympathetic and decreased parasympathetic nerve density in tumors were associated with poor clinical outcomes and correlated with higher expression of immune checkpoint molecules. These findings suggest that autonomic innervation of tumors regulates breast cancer progression.


Asunto(s)
Fibras Autónomas Preganglionares/patología , Neoplasias de la Mama/patología , Antagonistas Adrenérgicos/farmacología , Animales , Antígeno B7-H1/genética , Desnervación , Progresión de la Enfermedad , Femenino , Factores de Transcripción Forkhead/genética , Xenoinjertos , Humanos , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Sistema Nervioso Parasimpático/patología , Receptor de Muerte Celular Programada 1/genética , Ratas , Estudios Retrospectivos , Estrés Psicológico/psicología , Sistema Nervioso Simpático/patología
20.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-31340438

RESUMEN

Cancer immunotherapy has entered the forefront of cancer treatment, but major challenges still exist, such as the limited proportion of patients that respond to treatment and treatment-related toxicity. Therefore, biomarkers to predict which patients will benefit from therapy without major side effects are of the utmost importance. Moreover, novel therapeutic targets to increase the proportion of responding patients on a given immunotherapy or to alleviate immunotherapy-induced toxicity could be a valuable adjunct to immunotherapy treatment. Host factors such as age, obesity, and the composition of the gut microbiome have considerable effects on immune responses and, hence, could have a large impact on the outcome of immunotherapies. Moreover, since these host factors differ considerably between preclinical mouse models and human cancer patients, it might be possible that these host factors account, in part, for the observed discrepancies in outcomes between mice experiments and clinical trials. In this review, we discuss the latest data on the influence of aging, obesity, and the gut microbiome on the anti-tumor immune response and immunotherapy and propose avenues to increase our knowledge on this topic in order to improve patient selection for cancer immunotherapy treatment.


Asunto(s)
Envejecimiento/inmunología , Antineoplásicos Inmunológicos/uso terapéutico , Microbioma Gastrointestinal/inmunología , Regulación Neoplásica de la Expresión Génica , Inmunoterapia/métodos , Neoplasias/terapia , Obesidad/terapia , Envejecimiento/genética , Animales , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Biomarcadores Farmacológicos/análisis , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/inmunología , Modelos Animales de Enfermedad , Humanos , Ratones , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/microbiología , Obesidad/genética , Obesidad/inmunología , Obesidad/microbiología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Transducción de Señal
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