RESUMO
BACKGROUND: Tumor microenvironment is infiltrated by many immune cells, of which Regulatory T (Treg) cells are usually considered as negative regulators of the immune responses. However, the effect of FOXP3+ (forkhead box transcription factor 3) Treg cells infiltrated into the tumor areas on the prognosis of breast cancer is controversial. This meta-analysis aimed to dissect the potential values of FOXP3+ tumor-infiltrating lymphocytes (TILs) as a prognosis predictor of breast cancer. METHODS: After systematic retrieval of all relevant studies, 28 eligible articles were identified for meta-analysis. Odd ratio (OR), hazard ratio (HR), and 95% confidence interval (CI) were obtained for pooled analyses of pathological complete response (pCR), overall survival (OS), and corresponding forest plots and funnel plots were plotted, respectively. RESULTS: Pooled results revealed that patients with higher levels of FOXP3+ TILs experienced better pCR (OR: 1.24, 95% CI 1.09-1.41) and OS (HR: 0.79, 95% CI 0.64-0.97). Subgroup analysis revealed that elevated FOXP3+ TILs were significantly associated with improved pCR (OR: 1.20, 95% CI 1.02-1.40) and OS (HR: 0.22, 95% CI 0.06-0.88) in human epidermal growth factor receptor 2 positive (HER2+) breast cancer patients. Furthermore, FOXP3+ TILs in the stromal area were statistically correlated with the favorable pCR (OR: 1.22, 95% CI 1.08-1.38) and OS (HR: 0.68, 95% CI 0.49-0.96). CONCLUSIONS: The predictive role of FOXP3+ TILs in the prognosis of breast cancer is influenced by various factors such as molecular subtype of breast cancer and the location of Treg. In HER2+ breast cancer and triple-negative breast cancer, FOXP3+ TILs are associated with better pCR and OS. Additionally, FOXP3+ TILs in stromal represent a favourable prognosis.
Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias da Mama/patologia , Prognóstico , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Linfócitos T Reguladores/patologia , Fatores de Transcrição Forkhead/metabolismo , Microambiente TumoralRESUMO
OBJECTIVE: Liver cancer is the fifth most common cancer in the world. Research on the pathogenesis and detailed molecular mechanisms of liver cancer is very important. The immune system plays an important role in regulating the incidence and metastasis of liver cancer. MATERIALS AND METHODS: This work collected 20 blood samples from patients with clinical hepatocellular carcinoma without metastasis, 20 blood samples from patients with metastatic hepatocellular carcinoma, and 20 blood samples from healthy subjects. Flow cytometry was used to analyze the content of Treg and Th2 cells in the three groups of blood samples. Immunofluorescence was applied to analyze the relative expression of CTLA-4 and CD28 in lymphocytes of each group of blood samples. Western blot was used to analyze the T cell surface protein CTLA-4, CD28, GATA3, and FOXP3 expression in each group of blood samples. RESULTS: The expression of CD28 and GATA3 in the blood of patients with hepatocellular carcinoma without metastasis was obviously higher than that of patients with metastasis of hepatocellular carcinoma, which is contrary to the expression trend of CTLA-4 and FOXP3, and corresponds to the content ratio of Treg and Th2 cells, thus verifying the relationship between Treg/Th2 ratio and metastasis of hepatocellular carcinoma. CONCLUSIONS: In the microenvironment of liver cancer, the ratio of Treg/Th2 will increase significantly, thereby promoting the metastasis of hepatocellular carcinoma.
OBJETIVO: El cáncer de hígado es el quinto cáncer más común en el mundo. La investigación sobre la patogenia y los mecanismos moleculares detallados del cáncer de hígado es muy importante. El sistema inmunológico juega un papel importante en la regulación de la incidencia y metástasis del cáncer de hígado. MATERIAL Y MÉTODOS: Este trabajo recogió 20 muestras de sangre de pacientes con carcinoma hepatocelular clínico sin metástasis, 20 muestras de sangre de pacientes con carcinoma hepatocelular metastásico y 20 muestras de sangre de sujetos sanos. Se utilizó citometría de flujo para analizar el contenido de células Treg y Th2 en los tres grupos de muestras de sangre. Se aplicó inmunofluorescencia para analizar la expresión relativa de CTLA-4 y CD28 en linfocitos de cada grupo de muestras de sangre. Se utilizó Western blot para analizar la expresión de la proteína de superficie de células T CTLA-4, CD28, GATA3, FOXP3 en cada grupo de muestras de sangre. RESULTADOS: La expresión de CD28 y GATA3 en la sangre de pacientes con carcinoma hepatocelular sin metástasis fue obviamente mayor que la de pacientes con metástasis de carcinoma hepatocelular, lo cual es contrario a la tendencia de expresión de CTLA-4 y FOXP3, y corresponde al contenido relación de células Treg y Th2, verificando así la relación entre la relación Treg/Th2 y la metástasis del carcinoma hepatocelular. CONCLUSIONES: En el microambiente del cáncer de hígado, la proporción de Treg/Th2 aumentará significativamente, promoviendo así la metástasis del carcinoma hepatocelular.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/patologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Microambiente TumoralRESUMO
The immune system plays a key role in the protective response against oral cancer; however, the tumor microenvironment (TME) impairs this anti-cancer response by modulating T helper (Th) responses and promoting an anti-inflammatory environment. Regulatory T cells (Tregs) and Th2 effector cells (Teff) are associated with poor prognosis in oral squamous cell carcinoma (OSCC). However, the main immunomodulatory mechanisms associated with the enrichment of these subsets in OSCC remain unknown. We characterized Th-like lineages in Tregs and Teff and evaluated immunomodulatory changes induced by the TME in OSCC. Our phenotypic data revealed a higher distribution of tumour-infiltrating CCR8+ and Th2-like Treg in OSCC compared with non-malignant samples, whereas the percentages of Th1 cells were reduced in cancer. We then analyzed the direct effect of the TME by exposing T cell subsets to cancer secretomes and observed the OSCC secretome induced CCR8 expression and reduced cytokine production from both subsets. Transcriptomic analysis showed that the co-culture with OSCC secretome induced several gene changes associated with the vitamin D (VitD) signaling pathway in T cells. In addition, proteomic analysis identified the presence of several proteins associated with prostaglandin E2 (PGE2) production by rapid membrane VitD signaling and a reduced presence of the VitD binding protein. Thus, we analyzed the effect of VitD and PGE2 and observed that VitD promotes a regulatory Th2-like response with CCR8 expression whilst PGE2 also modulated CCR8 but inhibited cytokine production in combination with VitD. Finally, we evaluated the presence of CCR8 ligand in OSCC and observed increased chemokine CCL18, which was also able to upregulate CCR8 in activated Th cells. Overall, our data showed the immunomodulatory changes induced by the TME involving CCR8 expression and regulatory Th2 phenotypes, which are associated with PGE2 mediated VitD signaling pathway and CCL18 expression in OSCC.
Assuntos
Regulação Neoplásica da Expressão Gênica/imunologia , Imunomodulação , Neoplasias Bucais/imunologia , Proteínas de Neoplasias/imunologia , Receptores CCR8/imunologia , Transdução de Sinais/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Microambiente Tumoral/imunologia , Vitamina D/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Linfócitos T Reguladores/patologia , Células Th2/patologiaRESUMO
Colorectal cancer (CRC) represents the third most common malignancy and the second leading cause of cancer-related deaths worldwide. Although immunotherapy has taken center stage in mainstream oncology, it has shown limited clinical efficacy in CRC, generating an urgent need for discovery of new biomarkers and potential therapeutic targets. Galectin-1 (Gal-1), an endogenous glycan-binding protein, induces tolerogenic programs and contributes to tumor cell evasion of immune responses. Here, we investigated the relevance of Gal-1 in CRC and explored its modulatory activity within the CD8+ regulatory T cell (Treg) compartment. Mice lacking Gal-1 (Lgals1-/- ) developed a lower number of tumors and showed a decreased frequency of a particular population of CD8+CD122+PD-1+ Tregs in the azoxymethane-dextran sodium sulfate model of colitis-associated CRC. Moreover, silencing of tumor-derived Gal-1 in the syngeneic CT26 CRC model resulted in reduced number and attenuated immunosuppressive capacity of CD8+CD122+PD-1+ Tregs, leading to slower tumor growth. Moreover, stromal Gal-1 also influenced the fitness of CD8+ Tregs, highlighting the contribution of both tumor and stromal-derived Gal-1 to this immunoregulatory effect. Finally, bioinformatic analysis of a colorectal adenocarcinoma from The Cancer Genome Atlas dataset revealed a particular signature characterized by high CD8+ Treg score and elevated Gal-1 expression, which delineates poor prognosis in human CRC. Our findings identify CD8+CD122+PD-1+ Tregs as a target of the immunoregulatory activity of Gal-1, suggesting a potential immunotherapeutic strategy for the treatment of CRC.
Assuntos
Adenocarcinoma/genética , Linfócitos T CD8-Positivos/imunologia , Colite/genética , Neoplasias Colorretais/genética , Galectina 1/genética , Linfócitos T Reguladores/imunologia , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Animais , Atlas como Assunto , Azoximetano/administração & dosagem , Linfócitos T CD8-Positivos/patologia , Linhagem Celular Tumoral , Colite/induzido quimicamente , Colite/imunologia , Colite/mortalidade , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Biologia Computacional , Sulfato de Dextrana/administração & dosagem , Modelos Animais de Doenças , Galectina 1/deficiência , Galectina 1/imunologia , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade beta de Receptor de Interleucina-2/genética , Subunidade beta de Receptor de Interleucina-2/imunologia , Camundongos , Camundongos Knockout , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais , Análise de Sobrevida , Linfócitos T Reguladores/patologia , Carga TumoralRESUMO
The immune response is critical in NAFLD pathogenesis, but the liver infiltrate's composition and the role of each T cell population is still up for debate. To characterize liver pathogenesis in pediatric and adult cases, frequency and localization of immune cell populations [Cytotoxic T Lymphocytes (CD8+), T helper Lymphocytes (CD4+), Regulatory T lymphocytes (Foxp3+) and Th17 (IL-17A+)] were evaluated. In portal/periportal (P/P) tracts, both age groups displayed a similar proportion of CD8+ and CD4+ lymphocytes. However, comparable Foxp3+ and IL-17A+ cell frequencies were observed in pediatric cases, meanwhile, in adults Foxp3+ was higher than IL-17A+ cells. Interestingly, IL-17A+ lymphocytes seemed to be nearly exclusive of P/P area in both age groups. In intralobular areas, both pediatric and adult cases showed CD8+ lymphocytes predominance with lower frequencies of CD4+ lymphocytes followed by Foxp3+ . Severe inflammation was associated with higher intralobular Foxp3+ lymphocytes (p = 0.026) in children, and lower P/P Foxp3+ and higher IL-17A+ lymphocytes in adults. All cases with fibrosis ≥ 2 displayed P/P low Foxp3+ and high IL-17A+ lymphocyte counts. Pediatric cases with worse steatosis showed high P/P CD4+ (p = 0.023) and intralobular CD8+ (p = 0.027) and CD4+ cells (p = 0.012). In NAFLD cases, the lymphocyte liver infiltrate composition differs between histological areas. Treg and Th17 balance seems to condition damage progression, denoting their important role in pathogenesis.
Assuntos
Linhagem da Célula/imunologia , Fígado/imunologia , Hepatopatia Gordurosa não Alcoólica/genética , Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Linhagem da Célula/genética , Criança , Pré-Escolar , Feminino , Fatores de Transcrição Forkhead/genética , Humanos , Interleucina-17/genética , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/patologia , Pediatria , Linfócitos T/patologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Células Th1/imunologia , Células Th1/patologiaRESUMO
Dendritic cells (DCs) promote T-cell mediated tolerance to self-antigens and induce inflammation to innocuous-antigens. This dual potential makes DCs fundamental players in inflammatory disorders. Evidence from inflammatory colitis mouse models and inflammatory bowel diseases (IBD) patients indicated that gut inflammation in IBD is driven mainly by T-helper-1 (Th1) and Th17 cells, suggesting an essential role for DCs in the development of IBD. Here we show that GSK-J4, a selective inhibitor of the histone demethylase JMJD3/UTX, attenuated inflammatory colitis by reducing the inflammatory potential and increasing the tolerogenic features of DCs. Mechanistic analyses revealed that GSK-J4 increased activating epigenetic signals while reducing repressive marks in the promoter of retinaldehyde dehydrogenase isoforms 1 and 3 in DCs, enhancing the production of retinoic acid. This, in turn, has an impact on regulatory T cells (Treg) increasing their lineage stability and gut tropism as well as potentiating their suppressive activity. Our results open new avenues for the treatment of IBD patients.
Assuntos
Benzazepinas/farmacologia , Colite/imunologia , Células Dendríticas/imunologia , Doenças Inflamatórias Intestinais/imunologia , Pirimidinas/farmacologia , Tretinoína/imunologia , Família Aldeído Desidrogenase 1/genética , Família Aldeído Desidrogenase 1/imunologia , Animais , Colite/tratamento farmacológico , Colite/genética , Colite/patologia , Células Dendríticas/patologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Camundongos , Camundongos Knockout , Retinal Desidrogenase/genética , Retinal Desidrogenase/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Células Th1/imunologia , Células Th1/patologia , Células Th17/imunologia , Células Th17/patologiaRESUMO
BACKGROUND: Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numeric and/or functional TH cell alterations. The causes, interrelationships, and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia, autoantibody production, or both remain unclear. OBJECTIVE: We sought to determine how circulating CD4+ T cells are altered in CVID subjects with autoimmune cytopenias (AICs; CVID+AIC) and the causes of these derangements. METHODS: Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4+ T cells. Differences between subject groups were confirmed in a large and genetically diverse cohort of CVID subjects (n = 69) by using flow cytometry, transcriptional profiling, multiplex cytokine/chemokine detection, and a suite of in vitro functional assays measuring naive T-cell differentiation, B-cell/T-cell cocultures, and regulatory T-cell suppression. RESULTS: Although CD4+ TH cell profiles from healthy donors and CVID subjects without AICs were virtually indistinguishable, T cells from CVID+AIC subjects exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency-associated endotoxemia and endotoxin-induced expression of activin A and inducible T-cell costimulator ligand. The resulting enlarged circulating follicular helper T-cell population from CVID+AIC subjects provided efficient help to receptive healthy donor B cells but not unresponsive CVID B cells. Despite this, circulating follicular helper T cells from CVID+AIC subjects exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with regulatory T-cell suppression assays and were associated with autoantibody production. CONCLUSIONS: Endotoxemia is associated with early commitment to the follicular T-cell lineage in IgA-deficient CVID subjects, particularly those with AICs.
Assuntos
Linfócitos B/imunologia , Diferenciação Celular/imunologia , Imunodeficiência de Variável Comum/imunologia , Endotoxemia/imunologia , Deficiência de IgA/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Linfócitos B/patologia , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/patologia , Endotoxemia/patologia , Feminino , Humanos , Deficiência de IgA/patologia , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/patologiaRESUMO
H. pylori infection shows an inverse relationship with allergies. Dendritic cells regulate mucosal immune responses including the induction of T regulatory cells which are fundamental in Helicobacter pylori-induced dampening of allergies. In this respect expression of high-affinity IgE receptor (FcεRI) has been associated with a regulatory dendritic cell profile. Therefore we aimed to evaluate possible mechanisms by which H. pylori infection might modify atopy in pediatric patients. Here we show that H. pylori-infected children exhibited both increased expression of FcεRI on peripheral myeloid and plasmacytoid dendritic cells and higher levels of Foxp3 and Latency Associated Peptide on T regulatory cells. Moreover, exposure to H. pylori drove increased FcεRI expression and IL-10 secretion by both pediatric H. pylori-exposed monocyte derived dendritic cells and T cells. Finally, we show a positive correlation between expression of FcεRI in circulating myeloid DCs and total Treg cells, suggesting that in children, H. pylori infection may have a modulating role in atopy, mediated by both altered surface expression of FcεRI on children's DC and an increased T regulatory cell profile.
Assuntos
Células Dendríticas/metabolismo , Regulação da Expressão Gênica , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Receptores de IgE/metabolismo , Linfócitos T Reguladores/patologia , Adolescente , Criança , Feminino , Fatores de Transcrição Forkhead/metabolismo , Infecções por Helicobacter/sangue , Infecções por Helicobacter/patologia , Humanos , Tolerância Imunológica , Imunoglobulina E/sangue , Interleucina-10/metabolismo , Contagem de Linfócitos , Masculino , Linfócitos T Reguladores/metabolismoRESUMO
An important challenge in cancer immunotherapy is to expand the number of patients that benefit from immune checkpoint inhibitors (CI), a fact that has been related to the pre-existence of an efficient anti-tumor immune response. Different strategies are being proposed to promote tumor immunity and to be used in combined therapies with CI. Recently, we reported that intratumoral administration of naked poly A:U, a dsRNA mimetic empirically used in early clinical trials with some success, delays tumor growth and prolongs mice survival in several murine cancer models. Here, we show that CD103+ cDC1 and, to a much lesser extent CD11b+ cDC2, are the only populations expressing TLR3 at the tumor site, and consequently could be potential targets of poly A:U. Upon poly A:U administration these cells become activated and elicit profound changes in the composition of the tumor immune infiltrate, switching the immune suppressive tumor environment to anti-tumor immunity. The sole administration of naked poly A:U promotes striking changes within the lymphoid compartment, with all the anti-tumoral parameters being enhanced: a higher frequency of CD8+ Granzyme B+ T cells, (lower Treg/CD8+ ratio) and an important expansion of tumor-antigen specific CD8+ T cells. Also, PD1/PDL1 showed an increased expression indicating that neutralization of this axis could be exploited in combination with poly A:U. Our results shed new light to promote further assays in this dsRNA mimetic to the clinical field.