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1.
Nat Med ; 25(11): 1715-1720, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31700181

RESUMO

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.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Evolução Molecular , Genes MHC Classe I/genética , Variação Genética/genética , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Genes MHC Classe I/imunologia , Predisposição Genética para Doença , Variação Genética/imunologia , Genótipo , Humanos , Imunoterapia/efeitos adversos , Masculino , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética
2.
Scand J Immunol ; 90(6): e12821, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31589347

RESUMO

As a result of the cancer immunotherapy revolution, more than 2000 immuno-oncology agents are currently being tested or are in use to improve responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their development of cancer therapy by the blockade of co-inhibitory signals. Unfortunately, manipulation of the co-inhibitory receptors has also resulted in a safety issue: widespread iatrogenic immune-related adverse events (irAEs). Autoimmunity is emerging as the nemesis of immunotherapy. Originally, it was assumed that CTLA-4 blockade selectively targets T cells relevant to the antitumour immune response. However, an uncontrolled pan T cell activation was induced compromising tolerance to healthy self-tissues. The irAEs are very similar to that of a chronic graft-versus-host-disease (GVHD) reaction following allogeneic bone marrow transplantation (BMT). We hypothesized that ipilimumab induced a graft-versus-malignancy (GVM) effect, which eradicated metastatic melanoma in a minority of patients, but also involved an auto-GVHD reaction that resulted in widespread autoimmunity in the majority. Therefore, we argued for a profound theoretical point against the consensus of experts. The task is not to desperately put the genie back in the bottle by immune-suppressive treatments, but instead to harness the autoimmune forces. In this way, the same goal could be achieved by an antibody as by the adoptive transfer of alloreactive donor lymphocytes, but without severe GVHD. The proof-of-principle of a low-dose-combination immune checkpoint therapy, consisting only of approved drugs and treatments, was demonstrated in 111 stage IV cancer patients.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Autoimunidade/efeitos dos fármacos , Biomarcadores Tumorais/antagonistas & inibidores , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias/genética , Neoplasias/patologia , Uso Off-Label , Estudo de Prova de Conceito , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
3.
J Clin Neurosci ; 69: 31-37, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31473094

RESUMO

Abnormal CTLA-4 expression is involved in the development of myasthenia gravis (MG), and serum CTLA-4 levels are positively correlated with serum anti-AChR antibody concentration, which might be related with the severity of MG. Polymorphism in CTLA-4 gene is associated with various autoimmune disorders. We investigated the association of polymorphism in CTLA-4 gene with the clinical variables and severity of MG. The frequencies of alleles and genotypes were compared between 480 MG patients and 487 healthy controls, as well as among subgroups of MG patients. The frequency of rs733618*C allele is significantly higher in MG group and several subgroups than in control group. Genotype is not found as independent factor for essential clinical variables of MG. The frequency of rs231775*A allele is significantly lower in ocular onset subgroup than in control group, and the frequencies of rs231775*A allele and rs3087243*A allele are significantly lower in ocular onset subgroup than in generalized onset subgroup. Genotypes of the two SNPs are found as independent factors for ocular onset. The frequency of rs231775*A allele is significantly lower in mild subgroup than that in control group. Genotype is not found as independent factor for mild severity. A haplotype containing rs733618*C, rs231775*G and rs3087243*G is identified to increase the general risk of MG by 1.278-fold and ocular onset MG subgroup by 1.362-fold. There is association of rs733618 with the general susceptibility of MG, and association of rs231775 and rs3087243 with the susceptibility of ocular onset MG, but no association with the severity of MG.


Assuntos
Antígeno CTLA-4/genética , Predisposição Genética para Doença/genética , Miastenia Gravis/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
4.
Scand J Immunol ; 90(6): e12819, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31448426

RESUMO

Our aim was to evaluate the association of genetic polymorphisms of immunoregulatory molecules with susceptibility to hepatocellular carcinoma (HCC). The polymorphisms in CTLA-4 (-318 T/C, CT60 G/A), TNF (-238 G/A, -308 G/A) and IL10 (-592 C/A, -819 C/T) were genotyped by PCR and DNA sequencing. The functional relevance of the polymorphisms was examined by ELISAs, in vitro lymphocyte proliferation assay and cytotoxic assay. The CTLA-4 -318 TC/TT, CTLA-4 CT60 GG, IL10 -592 CA and -819 CT/TT variants, CTLA-4 -318 T and IL 10 -819 T alleles were positively associated with HCC risk (P < .05). While TNF -238 AA variant, TNF -238 A allele were associated with decreased risk of HCC (P < .05). Furthermore, combinations of CTLA-4 -318 TC/TT and TNF -238 GG/GA; CTLA-4 -318 TC/TT and IL 10 -819 CC; CTLA-4 -318 CC and IL 10 -819 CT/TT in patients with HCC were statistically significant (P < .05). Peripheral blood mononuclear cells (PBMCs) carrying -318 TC/TT genotypes exhibited significantly lower proliferation rates, decreased IL-2, IL-4 levels, fewer cytolytic activities and elevated TGF-ß levels. For IL 10 -819 C/T, the CC genotype was significantly associated with higher proliferation rate, decreased TGF-ß, IL-10 levels and higher cytolytic activities (P < .05). For TNF -238 G/A, the AA genotype only had association with serum IL-2, IL-4 (P < .05). In addition, we also found that CTLA-4 -318 T/C, IL-10 -819 T/C variants, combinations of CTLA-4 -318 CC with IL 10 -819 CT or TT, CTLA-4 -318 TC or TT with IL 10 -819 CT or TT were associated with the severity of HCC. These findings suggest that CTLA-4 -318 TC/TT and IL 10 -819 CT/TT could promote the pathogenesis of HCC, which might be related with down-regulation of Th1/Th2-type cytokines and/or up-regulation of Th3-type cytokines.


Assuntos
Antígeno CTLA-4/genética , Carcinoma Hepatocelular/genética , Interleucina-10/genética , Neoplasias Hepáticas/genética , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/genética , Adulto , Idoso , Alelos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Citocinas/metabolismo , Citotoxicidade Imunológica , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Linfócitos T/imunologia , Linfócitos T/metabolismo
5.
Nat Commun ; 10(1): 3216, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324808

RESUMO

Thousands of genetic variants are associated with human disease risk, but linkage disequilibrium (LD) hinders fine-mapping the causal variants. Both lack of power, and joint tagging of two or more distinct causal variants by a single non-causal SNP, lead to inaccuracies in fine-mapping, with stochastic search more robust than stepwise. We develop a computationally efficient multinomial fine-mapping (MFM) approach that borrows information between diseases in a Bayesian framework. We show that MFM has greater accuracy than single disease analysis when shared causal variants exist, and negligible loss of precision otherwise. MFM analysis of six immune-mediated diseases reveals causal variants undetected in individual disease analysis, including in IL2RA where we confirm functional effects of multiple causal variants using allele-specific expression in sorted CD4+ T cells from genotype-selected individuals. MFM has the potential to increase fine-mapping resolution in related diseases enabling the identification of associated cellular and molecular phenotypes.


Assuntos
Autoimunidade/genética , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Alelos , Teorema de Bayes , Linfócitos T CD4-Positivos , Antígeno CTLA-4/genética , Mapeamento Cromossômico , Regulação da Expressão Gênica , Genótipo , Humanos , Subunidade alfa de Receptor de Interleucina-2/genética , Desequilíbrio de Ligação , Fenótipo , Polimorfismo de Nucleotídeo Único
6.
J Clin Pathol ; 72(10): 659-662, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31340988

RESUMO

CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) or CD152 is an inhibitory receptor expressed constitutively on CD4+ CD25+ T regulatory lymphocytes and transiently on activated CD4+ and CD8+ T lymphocytes. Its inhibitory function promotes long-lived anergy in immune cells and prevents autoimmunity. Therefore, it plays a crucial role in T cell-mediated autoimmunity, and thus in susceptibility to autoimmune diseases, including systemic lupus erythematosus (SLE). It is encoded by CTLA4 gene in humans. AtoG polymorphism at position +49 of CTLA4 gene is the only polymorphism which changes amino acid sequence from alanine to threonine in the leader sequence, which may affect the function of CTLA-4. Association of CTLA4 polymorphisms with SLE has been investigated in several reports in different ethnic populations from different countries, which have shown highly inconsistent findings. In this review, we have compiled previous studies which have reported the association of CTLA4 A49G polymorphism in SLE and its geographical distribution.


Assuntos
Antígeno CTLA-4/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único/genética , Autoimunidade , Predisposição Genética para Doença , Geografia , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Linfócitos T Reguladores/imunologia
7.
Medicine (Baltimore) ; 98(29): e16266, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335675

RESUMO

It has been proposed that cytotoxic T-lymphocyte antigen 4 (CTLA-4) may attenuate the T-cell activation threshold, thereby decreasing the antitumor response and conferring susceptibility to hepatocellular carcinoma (HCC).In the present study, we selected CTLA-4 tagging single nucleotide polymorphisms (SNPs) and explored the relationship between these polymorphisms and susceptibility to HCC. A hospital-based case-control study, comprising 584 cases with HCC and 923 controls, was performed in an eastern Chinese Han population. CTLA-4 SNPs were genotyped using a custom-by-design 48-Plex SNPscan Kit.We found that the CTLA-4 rs3087243 G>A polymorphism might be associated with increased risk of HCC (GA vs GG: adjusted odds ratio [OR], 1.38; 95% confidence interval [CI], 1.04-1.85; P = .028 and AA/GA vs GG: adjusted OR, 1.43; 95% CI, 1.08-1.89; P = .012). After using Bonferroni correction, this association remained (P = .012 for the AA/GA vs GG genetic model). In addition, the power value was 0.904 in the AA/GA versus GG genetic model. Haplotype analysis showed that CTLA4 Crs16840252Ars231775Ars3087243Trs733618, Crs16840252Grs231775Ars3087243Trs733618, and other haplotypes might increase the risk of HCC risk (P = .018, <.001, and .017, respectively). However, we found that CTLA4 Trs16840252A rs231775Grs3087243Trs733618 decreased the risk of HCC (P = .020).Our results suggest that the CTLA-4 rs3087243 G>A polymorphism increases susceptibility to HCC in an eastern Chinese Han population. CTLA-4 haplotypes may influence the development of HCC. In the future, a population-based fine-mapping study with functional assessment should be performed to further determine these potential correlations.


Assuntos
Antígeno CTLA-4/genética , Carcinoma Hepatocelular , Neoplasias Hepáticas , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
8.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340438

RESUMO

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.


Assuntos
Envelhecimento/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Microbioma Gastrointestinal/imunologia , Regulação Neoplásica da Expressão Gênica , Imunoterapia/métodos , Neoplasias/terapia , Obesidade/terapia , Envelhecimento/genética , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Biomarcadores Farmacológicos/análise , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Modelos Animais de Doenças , Humanos , Camundongos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/microbiologia , Obesidade/genética , Obesidade/imunologia , Obesidade/microbiologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais
9.
Arch Immunol Ther Exp (Warsz) ; 67(5): 335-349, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31177287

RESUMO

Major causes of chronic kidney disease are primary proliferative and nonproliferative glomerulonephritides (PGN and NPGN). However, the pathogenesis of PGN and NPGN is still not fully understood. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a T-cell membrane receptor that plays a key role in T-cell inhibition. Despite its role in autoimmunological diseases, little is known about the involvement of CTLA-4 in the pathogenesis of PGN and NPGN. The objective of this study was to determine the role of CTLA-4 in the pathogenesis of PGN and NPGN by evaluating the frequencies of T and B lymphocytes expressing CTLA-4 and the serum concentration of the sCTLA-4 isoform in patients with PGN and NPGN in relation to clinical parameters. The study included peripheral blood (PB) samples from 40 PGN and NPGN patients and 20 healthy age- and sex-matched volunteers (control group). The viable PB lymphocytes were labeled with fluorochrome-conjugated monoclonal anti-CTLA-4 antibodies and analyzed using flow cytometry. The serum concentration of sCTLA-4 was measured using ELISA. The frequencies and absolute counts of CD4+/CTLA-4+ T lymphocytes, CD8+/CTLA-4+ T lymphocytes and CD19+/CTLA-4+ B lymphocytes and the serum sCTLA-4 concentration were lower in PGN and NPGN patients that in the control group. Reduced sCTLA-4 expression was associated with a lower concentration of serum immunoglobulins. Our results indicate that deregulation of CTLA-4 expression may result in continuous activation of T cells and contribute to the pathogenesis of PGN and NPGN.


Assuntos
Antígeno CTLA-4/genética , Regulação da Expressão Gênica , Glomerulonefrite/imunologia , Glomerulonefrite/fisiopatologia , Imunoglobulinas/sangue , Rim/fisiopatologia , Subpopulações de Linfócitos/metabolismo , Adulto , Idoso , Antígenos CD/metabolismo , Antígeno CTLA-4/sangue , Antígeno CTLA-4/metabolismo , Feminino , Humanos , Ativação Linfocitária , Contagem de Linfócitos , Subpopulações de Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Curva ROC , Adulto Jovem
10.
J Oral Pathol Med ; 48(8): 669-676, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31132187

RESUMO

BACKGROUND: Since the inhibitory immune checkpoint receptors have been described to benefit the OSCC patients clinically, it is unknown that whether their expression in tumor immune microenvironment (TME) can determine the clinical outcome in response to nimotuzumab therapy. METHODS: We examined the expression patterns of immune checkpoint receptors (including TIM-3, LAG-3, PD-L1, and CTLA-4) and an immunoregulatory enzyme called IDO in 36 OSCC patients during nimotuzumab therapy by immunohistochemistry. Then, we divided the recruited patients into clinical responders and non-responders according to computed tomography (CT) scan and analyzed the relationship between the immunological parameters and clinical outcome. RESULTS: We observed that nimotuzumab therapy significantly increased the expression of TIM-3, LAG-3, IDO, PD-L1, and CTLA-4 in the TME, and the expression of LAG-3 and PD-L1 before nimotuzumab therapy was inversely correlated with the overall survival. In clinical non-responders, we found the expression of TIM-3, LAG-3, IDO, PD-L1, and CTLA-4 was significantly increased during nimotuzumab therapy, and the expression of TIM-3, LAG-3, IDO, PD-L1, and CTLA-4 before nimotuzumab therapy was negatively correlated with the overall survival. However, in clinical responders, neither of those showed significant. CONCLUSIONS: It suggests that these immune checkpoint receptors and IDO could be considered as biomarkers to reflect immune status in the tumor microenvironment during nimotuzumab therapy. Blockade of these immune checkpoint receptors might enhance nimotuzumab-based cancer immunotherapy, thus potentially improving clinical outcomes of OSCC patients.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Neoplasias Bucais/tratamento farmacológico , Antígenos CD/genética , Antígeno B7-H1/genética , Antígeno CTLA-4/genética , Carcinoma de Células Escamosas/genética , Feminino , Receptor Celular 2 do Vírus da Hepatite A/genética , Humanos , Imunoterapia , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Prognóstico , Microambiente Tumoral
11.
Immunol Invest ; 48(6): 659-671, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31094250

RESUMO

Each functional gene illustrates the complexity of genetic predisposition to disease; however, it is difficult to bring out these traits with reference to autoimmune diseases like type 1 diabetes (T1D). To find out the genetic contribution of CTLA-4 + 49A/G, CTLA-4 -318C/T and CD28 + 17T/C polymorphisms toward T1D, the present study was performed with 124 T1D patients, 54 siblings and 125 parents including 39 trios in South Indian population. The association and linkage of CTLA-4 + 49A/G, CTLA-4 -318C/T and CD28 + 17T/C polymorphisms with T1D were analyzed and transmission disequilibrium test was performed. CTLA-4 G allele carrying genotypes (GG+AG) showed a higher risk association and can be considered as susceptible to develop T1D among patients with age at diagnosis from 0 to 10 years as compared to siblings (OR = 2.9; pc = 0.047) and parents (OR = 2.7; pc = 0.036). On the other hand, a strong protection against the disease (age at diagnosis; 0-10 years) was observed with CTLA-4 + 49AA genotype (OR = 0.37; pc = 0.036) and combined AA/CC genotype (OR = 0.31; pc = 0.034) of CTLA-4 + 49A/G and CTLA-4 -318C/T polymorphisms. However, a significant association was not observed between CTLA-4 -318C/T and CD28 + 17T/C polymorphisms and T1D. This family-based study reports a strong association between possible genotypes of CTLA-4 gene polymorphism and T1D in South Indian population, particularly in younger individuals.


Assuntos
Antígenos CD28/genética , Antígeno CTLA-4/genética , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Adolescente , Adulto , Fatores Etários , Criança , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Índia , Masculino , Polimorfismo Genético , Risco , Adulto Jovem
12.
Anticancer Res ; 39(4): 1997-2005, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952743

RESUMO

BACKGROUND/AIM: Immune checkpoint inhibitors are mainly used for right-sided, microsatellite instability-high colorectal tumors. In this study, the effects of oral uracil-tegafur plus leucovorin (UFT/LV) chemotherapy on the gene expressions of four immunotherapy targets and the amounts of tumor-infiltrating lymphocytes (TILs) were investigated. PATIENTS AND METHODS: Data of 260 patients with stage II or stage III colorectal cancer were analyzed. Gene expression and amount of TILs were evaluated using real-time reverse transcription polymerase chain reaction (CRT-PCR) assay and immunohistochemical staining, respectively. RESULTS: Expression of CTLA4 and LAG3 in tumor tissues was significantly increased after UFT/LV chemotherapy, but only in left-sided tumors. The percentage of high-TIL, high-CD3 and high-FoxP3 patients in the UFT/LV group was significantly higher than that in the control group, only in left-sided tumors. CONCLUSION: The increase in TILs count, especially of CD3+ T cells and FoxP3+ regulatory T cells, after UFT/LV chemotherapy were specific to left-sided colorectal cancers.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Complexo CD3/imunologia , Neoplasias Colorretais/imunologia , Fatores de Transcrição Forkhead/imunologia , Leucovorina/administração & dosagem , Linfócitos T/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Antígeno CTLA-4/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologia , Tegafur/administração & dosagem , Uracila/administração & dosagem
13.
Endocr J ; 66(4): 295-300, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-30814440

RESUMO

Therapeutic blocking antibodies against programmed death 1 (PD1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) are applied for advanced cancer therapy, but induce a wide range of immune-related adverse events. In our recent case of a 52-year-old female doctor suffering from breast cancer having metastasized to the lung and liver, it was decided to use nivolumab to prevent the disease progressing after excisional surgeries and multiple chemotherapies. One month after completing the nivolumab course, fatigue, hypoglycemia and hypotension developed and isolated ACTH deficiency (IAD) was diagnosed. A further month later, under steroid supplementation, hyperglycemia emerged alongside thirst and polydipsia, prompting a diagnosis of fulminant type 1 diabetes (FT1D). Her susceptibility to type 1 diabetes was examined by HLA haplotype and CTLA4 gene polymorphism analyses. Polymorphisms CT60G>A and +49G>A in CTLA4 both generated a GG genotype. Our patient manifested one of the rarest combinations of autoimmune disease induced by nivolumab. Whereas the HLA haplotype was unsusceptible to autoimmune type 1 diabetes, polymorphisms of CTLA4, the antibody of which frequently causes hypophysitis, were susceptible to FT1D. Peripheral modulation of activated T cells, mainly by PD-1 antibodies, induced FT1D associated with IAD in patients with CTLA4 polymorphism. This case reveals hints of the T-cell etiology in T1D and evidence of CTLA4 involvement in IAD.


Assuntos
Hormônio Adrenocorticotrópico/deficiência , Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Diabetes Mellitus Tipo 1/etiologia , Doenças do Sistema Endócrino/induzido quimicamente , Doenças Genéticas Inatas/induzido quimicamente , Hipoglicemia/induzido quimicamente , Nivolumabe/efeitos adversos , Antígeno CTLA-4/genética , Doenças do Sistema Endócrino/complicações , Feminino , Doenças Genéticas Inatas/complicações , Humanos , Hipoglicemia/complicações , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
14.
J Immunol ; 202(9): 2806-2816, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30910862

RESUMO

The clinical benefit of CTLA-4 blockade on T cells is known, yet the impact of its expression on cancer cells remains unaddressed. We define an immunosuppressive role for tumor-expressed CTLA-4 using chronic lymphocytic leukemia (CLL) as a disease model. CLL cells, among other cancer cells, are CTLA-4+ Coculture with activated human T cells induced surface CTLA-4 on primary human CLL B cells. CTLA-4 on CLL-derived human cell lines decreased CD80 expression on cocultured CD80+ cells, with restoration upon CTLA-4 blockade. Coculture of CTLA-4+ CLL cells with CD80-GFP+ cell lines revealed transfer of CD80-GFP into CLL tumor cells, similar to CTLA-4+ T cells able to trans-endocytose CD80. Coculture of T cells with CTLA-4+ CLL cells decreased IL-2 production. Using a human CTLA-4 knock-in mouse lacking FcγR function, antitumor efficacy was observed by blocking murine CTLA-4 on tumor cells in isolation of the T cell effect and Fc-mediated depletion. These data implicate tumor CTLA-4 in cancer cell-mediated immunosuppression in vitro and as having a functional role in tumor cells in vivo.


Assuntos
Linfócitos B/imunologia , Antígeno CTLA-4/imunologia , Tolerância Imunológica , Leucemia Linfocítica Crônica de Células B/imunologia , Proteínas de Neoplasias/imunologia , Linfócitos T/imunologia , Animais , Linfócitos B/patologia , Antígeno CTLA-4/genética , Linhagem Celular Tumoral , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Receptores de IgG/genética , Receptores de IgG/imunologia , Linfócitos T/patologia
15.
Nat Commun ; 10(1): 1065, 2019 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-30911002

RESUMO

The major cause of death after allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for acute myeloid leukemia (AML) is disease relapse. We investigated the expression of Inhibitory Receptors (IR; PD-1/CTLA-4/TIM-3/LAG-3/2B4/KLRG1/GITR) on T cells infiltrating the bone marrow (BM) of 32 AML patients relapsing (median 251 days) or maintaining complete remission (CR; median 1 year) after HSCT. A higher proportion of early-differentiated Memory Stem (TSCM) and Central Memory BM-T cells express multiple IR in relapsing patients than in CR patients. Exhausted BM-T cells at relapse display a restricted TCR repertoire, impaired effector functions and leukemia-reactive specificities. In 57 patients, early detection of severely exhausted (PD-1+Eomes+T-bet-) BM-TSCM predicts relapse. Accordingly, leukemia-specific T cells in patients prone to relapse display exhaustion markers, absent in patients maintaining long-term CR. These results highlight a wide, though reversible, immunological dysfunction in the BM of AML patients relapsing after HSCT and suggest new therapeutic opportunities for the disease.


Assuntos
Anergia Clonal , Regulação Leucêmica da Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Memória Imunológica/genética , Leucemia Mieloide Aguda/imunologia , Linfócitos T/imunologia , Adulto , Antígenos CD/genética , Antígenos CD/imunologia , Antineoplásicos/uso terapêutico , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Feminino , Proteína Relacionada a TNFR Induzida por Glucocorticoide/genética , Proteína Relacionada a TNFR Induzida por Glucocorticoide/imunologia , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptores KIR/genética , Receptores KIR/imunologia , Recidiva , Indução de Remissão , Estudos Retrospectivos , Transdução de Sinais , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia , Linfócitos T/patologia , Transplante Homólogo
16.
DNA Cell Biol ; 38(5): 443-448, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30888206

RESUMO

Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a key negative immunoregulatory molecule with characteristics of gene polymorphisms. Genetically predisposed CTLA-4 alteration in humans was associated with gastric cancer (GC) development. To explore the association of CTLA-4 polymorphism with susceptibility of noncardiac GC (NCGC), 490 NCGC patients and 1476 control individuals were studied. Four CTLA-4 polymorphisms were genotyped with SNPscan genotyping assays and the haplotypes were constructed with SHESIS software. Frequencies of the CTLA-4 haplotypes were estimated using an expectation-maximization algorithm. The CTLA-4 polymorphism genotype distribution and allele frequencies were not significantly different between the NCGC patients and the control subjects. The CTLA-4 haplotypes did not exhibit a significantly increased risk for NCGC patients. Adjusting status of age, sex, smoking status, alcohol use, and body mass index could not moderate any of the relationships. Data suggested that CTLA-4 polymorphisms (rs3087243, rs16840252, rs733618, and rs231775) were not significantly associated with the risk of NCGC in this Chinese population studied.


Assuntos
Antígeno CTLA-4/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias Gástricas/genética , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
17.
Immunity ; 50(4): 1084-1098.e10, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30926234

RESUMO

Co-stimulation regulates T cell activation, but it remains unclear whether co-stimulatory pathways also control T cell differentiation. We used mass cytometry to profile T cells generated in the genetic absence of the negative co-stimulatory molecules CTLA-4 and PD-1. Our data indicate that negative co-stimulation constrains the possible cell states that peripheral T cells can acquire. CTLA-4 imposes major boundaries on CD4+ T cell phenotypes, whereas PD-1 subtly limits CD8+ T cell phenotypes. By computationally reconstructing T cell differentiation paths, we identified protein expression changes that underlied the abnormal phenotypic expansion and pinpointed when lineage choice events occurred during differentiation. Similar alterations in T cell phenotypes were observed after anti-CTLA-4 and anti-PD-1 antibody blockade. These findings implicate negative co-stimulation as a key regulator and determinant of T cell differentiation and suggest that checkpoint blockade might work in part by altering the limits of T cell phenotypes.


Assuntos
Antígeno CTLA-4/imunologia , Ativação Linfocitária , Linfopoese , Receptor de Morte Celular Programada 1/imunologia , Subpopulações de Linfócitos T/citologia , Animais , Linfócitos T CD4-Positivos/classificação , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/deficiência , Antígeno CTLA-4/genética , Linhagem da Célula , Imunofenotipagem , Linfonodos/citologia , Camundongos Knockout , Timo/citologia
18.
Int Immunopharmacol ; 71: 267-276, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30927737

RESUMO

High expression levels of miR-155 are involved in the pathogenesis of inflammatory bowel disease (IBD). We observed an increase in miR-155 in peripheral regulatory T (Treg) cells from IBD patients. Mice that specifically overexpress miR-155 in Foxp3+ Treg cells exhibit spontaneous autoimmunity and more severe dextran sulfate sodium (DSS)-induced intestinal injury. MiR-155 overexpression can lead to a lack of follicular Treg (Tfr) cells and central Treg (cTreg), whereas DSS treatment further depletes the Tfr cells. Furthermore, miR-155 can target the expression of CTLA-4 in cTreg and Tfr, directly inhibiting Tfr cell production and promoting enhanced germinal center (GC) B cell activation and autoantibody overproduction. This outcome may be the cause of severe intestinal injury in patients with autoimmune IBD.


Assuntos
Linfócitos B/imunologia , Colite/genética , Centro Germinativo/imunologia , Doenças Inflamatórias Intestinais/genética , MicroRNAs/genética , Linfócitos T Reguladores/imunologia , Animais , Formação de Anticorpos , Autoanticorpos/sangue , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos
19.
Mol Cancer ; 18(1): 32, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30823926

RESUMO

Exosomes are small extracellular vesicles that contain genetic material, proteins, and lipids. They function as potent signaling molecules between cancer cells and the surrounding cells that comprise the tumor microenvironment (TME). Exosomes derived from both tumor and stromal cells have been implicated in all stages of cancer progression and play an important role in therapy resistance. Moreover, due to their nature as mediators of cell-cell communication, they are integral to TME-dependent therapy resistance. In this review, we discuss current exosome isolation and profiling techniques and their role in TME interactions and therapy resistance. We also explore emerging clinical applications of both exosomes as biomarkers, direct therapeutic targets, and engineered nanocarriers. In order to fully understand the TME, careful interrogation of exosomes and their cargo is critical. This understanding is a promising avenue for the development of effective clinical applications.


Assuntos
Biomarcadores Tumorais/imunologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Exossomos/imunologia , Neoplasias/imunologia , Microambiente Tumoral/imunologia , Anticorpos Neutralizantes/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/química , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia , Comunicação Celular/imunologia , Progressão da Doença , Portadores de Fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Células Endoteliais/patologia , Exossomos/química , Exossomos/transplante , Humanos , Imunoterapia/métodos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Neoplasias/genética , Neoplasias/patologia , Neoplasias/terapia , Células Estromais/efeitos dos fármacos , Células Estromais/imunologia , Células Estromais/patologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
20.
PLoS One ; 14(2): e0211866, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30735560

RESUMO

Personalised medicine targeted to specific biomarkers such as BRAF and c-Kit has radically improved the success of melanoma therapy. More recently, further advances have been made using therapies targeting the immune response. In particular, therapies targeting the PD-1/PD-L1 or CTLA-4 axes alone or in combination have shown more sustained responses in 30-60% of patients. However, these therapies are associated with considerable toxicities and useful biomarkers to predict responders and non-responders are slow to emerge. Here we developed a reliable melanoma circulating tumor cell (CTC) detection method with PD-L1 evaluation on CTCs. A set of melanoma cell surface markers was tested as candidates for targeted melanoma CTC isolation and a melanoma specific immunostaining-based CTC identification protocol combined with PD-L1 detection was established. In vitro testing of the effect of exposure to blood cells on melanoma cell PD-L1 expression was undertaken. Immunomagnetic targeting isolated melanoma CTCs in up to 87.5% of stage IV melanoma patient blood samples and 3 8.6% of these had some PD-L1 expressing CTCs. Our in vitro data demonstrate PD-L1 induction on melanoma cells in the blood.This study established a robust, reliable method to isolate melanoma CTCs and detect expression of PD-L1 on these cells.


Assuntos
Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Separação Imunomagnética/métodos , Neoplasias Pulmonares/diagnóstico , Melanoma/diagnóstico , Neoplasias Cutâneas/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/sangue , Biomarcadores Tumorais/sangue , Antígeno CTLA-4/sangue , Antígeno CTLA-4/genética , Feminino , Humanos , Imunofenotipagem , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Masculino , Melanoma/sangue , Melanoma/genética , Melanoma/secundário , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Células Neoplásicas Circulantes/imunologia , Células Neoplásicas Circulantes/patologia , Receptor de Morte Celular Programada 1/sangue , Receptor de Morte Celular Programada 1/genética , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
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