RESUMEN
Concurrent chemoradiotherapy (CRT) with blockade of the PD-1 pathway may enhance immune-mediated tumor control through increased phagocytosis, cell death, and antigen presentation. The NiCOL phase 1 trial (NCT03298893) is designed to determine the safety/tolerance profile and the recommended phase-II dose of nivolumab with and following concurrent CRT in 16 women with locally advanced cervical cancer. Secondary endpoints include objective response rate (ORR), progression free survival (PFS), disease free survival, and immune correlates of response. Three patients experience grade 3 dose-limiting toxicities. The pre-specified endpoints are met, and overall response rate is 93.8% [95%CI: 69.8-99.8%] with a 2-year PFS of 75% [95% CI: 56.5-99.5%]. Compared to patients with progressive disease (PD), progression-free (PF) subjects show a brisker stromal immune infiltrate, higher proximity of tumor-infiltrating CD3+ T cells to PD-L1+ tumor cells and of FOXP3+ T cells to proliferating CD11c+ myeloid cells. PF show higher baseline levels of PD-1 and ICOS-L on tumor-infiltrating EMRA CD4+ T cells and tumor-associated macrophages, respectively; PD instead, display enhanced PD-L1 expression on TAMs, higher peripheral frequencies of proliferating Tregs at baseline and higher PD-1 levels at week 6 post-treatment initiation on CD4 and CD8 T cell subsets. Concomitant nivolumab plus definitive CRT is safe and associated with encouraging PFS rates. Further validation in the subset of locally advanced cervical cancer displaying pre-existing, adaptive immune activation is warranted.
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Neoplasias Pulmonares , Neoplasias del Cuello Uterino , Humanos , Femenino , Nivolumab/uso terapéutico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Antígeno B7-H1 , Receptor de Muerte Celular Programada 1 , Quimioradioterapia , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
The tumor associated macrophages (TAM) represent one of most abundant subpopulations across several solid cancers and their number/frequency is associated with a poor clinical outcome. It has been clearly demonstrated that stromal cells, such as the cancer associated fibroblasts (CAFs), may orchestrate TAM recruitment, survival and reprogramming. Today, single cell-RNA sequencing (sc-RNA seq) technologies allowed a more granular knowledge about TAMs and CAFs phenotypical and functional programs. In this mini-review we discuss the recent discoveries in the sc-RNA seq field focusing on TAM and CAF identity and their crosstalk in the tumor microenvironment (TME) of solid cancers.
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Fibroblastos Asociados al Cáncer , Neoplasias , Fibroblastos Asociados al Cáncer/patología , Macrófagos Asociados a Tumores , Células del Estroma , Neoplasias/patologíaRESUMEN
Tumor-associated macrophages (TAM) play a detrimental role in triple-negative breast cancer (TNBC). In-depth analysis of TAM characteristics and interactions with stromal cells, such as cancer-associated fibroblast (CAF), could provide important biological and therapeutic insights. Here we identify at the single-cell level a monocyte-derived STAB1+TREM2high lipid-associated macrophage (LAM) subpopulation with immune suppressive capacities that is expanded in patients resistant to immune checkpoint blockade (ICB). Genetic depletion of this LAM subset in mice suppressed TNBC tumor growth. Flow cytometry and bulk RNA sequencing data demonstrated that coculture with TNBC-derived CAFs led to reprogramming of blood monocytes towards immune suppressive STAB1+TREM2high LAMs, which inhibit T-cell activation and proliferation. Cell-to-cell interaction modeling and assays in vitro demonstrated the role of the inflammatory CXCL12-CXCR4 axis in CAF-myeloid cell cross-talk and recruitment of monocytes in tumor sites. Altogether, these data suggest an inflammation model whereby monocytes recruited to the tumor via the CAF-driven CXCL12-CXCR4 axis acquire protumorigenic LAM capacities to support an immunosuppressive microenvironment. SIGNIFICANCE: This work identifies a novel lipid-associated macrophage subpopulation with immune suppressive functions, offering new leads for therapeutic interventions in triple-negative breast cancer.
Asunto(s)
Fibroblastos Asociados al Cáncer , Neoplasias de la Mama Triple Negativas , Animales , Fibroblastos Asociados al Cáncer/patología , Moléculas de Adhesión Celular Neuronal , Línea Celular Tumoral , Fibroblastos/patología , Humanos , Inhibidores de Puntos de Control Inmunológico , Lípidos , Macrófagos , Ratones , Neoplasias de la Mama Triple Negativas/patología , Microambiente Tumoral/genéticaRESUMEN
Tumor associated macrophages (TAMs), which differentiate from circulating monocytes, are pervasive across human cancers and comprise heterogeneous populations. The contribution of tumor-derived signals to TAM heterogeneity is not well understood. In particular, tumors release both soluble factors and extracellular vesicles (EVs), whose respective impact on TAM precursors may be different. Here, we show that triple negative breast cancer cells (TNBCs) release EVs and soluble molecules promoting monocyte differentiation toward distinct macrophage fates. EVs specifically promoted proinflammatory macrophages bearing an interferon response signature. The combination in TNBC EVs of surface CSF-1 promoting survival and cargoes promoting cGAS/STING or other activation pathways led to differentiation of this particular macrophage subset. Notably, macrophages expressing the EV-induced signature were found among patients' TAMs. Furthermore, higher expression of this signature was associated with T cell infiltration and extended patient survival. Together, this data indicates that TNBC-released CSF-1-bearing EVs promote a tumor immune microenvironment associated with a better prognosis in TNBC patients.
Asunto(s)
Vesículas Extracelulares , Neoplasias de la Mama Triple Negativas , Vesículas Extracelulares/fisiología , Humanos , Macrófagos , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
CD39 is an enzyme which is responsible, together with CD73, for a cascade converting adenosine triphosphate into adenosine diphosphate and cyclic adenosine monophosphate, ultimately leading to the release of an immunosuppressive form of adenosine in the tumor microenvironment. Here, we first review the environmental and genetic factors shaping CD39 expression. Second, we report CD39 functions in the T cell compartment, highlighting its role in regulatory T cells, conventional CD4+ T cells and CD8+ T cells. Finally, we compile a list of studies, from preclinical models to clinical trials, which have made essential contributions to the discovery of novel combinatorial approaches in the treatment of cancer.
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Antígenos CD/metabolismo , Apirasa/metabolismo , Linfocitos T/metabolismo , Animales , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos CD/fisiología , Apirasa/genética , Apirasa/inmunología , Apirasa/fisiología , Regulación de la Expresión Génica , Humanos , Linfocitos T/inmunologíaRESUMEN
OBJECTIVES: Type I interferons (IFNs) inhibit regulatory T-cell (Treg) expansion and activation, making them beneficial in antiviral responses, but detrimental in autoimmune diseases. Herein, we investigate the role of ISG15 in human Tregs in the context of refractoriness to type I IFN stimulation. METHODS: ISG15 expression and Treg dynamics were analysed in vitro and ex vivo from patients with chronic hepatitis C, with lupus and ISG15 deficiency. RESULTS: ISG15 is expressed at high levels in human Tregs, renders them refractory to the IFN-STAT1 signal, and protects them from IFN-driven contraction. In vitro, Tregs from healthy controls upregulate ISG15 upon activation to higher levels than conventional CD4 T cells, and ISG15-silenced Tregs are more susceptible to IFNα-induced contraction. In human ISG15 deficiency, patient Tregs display an elevated IFN signature relative to Tregs from healthy control. In vivo, in patients with chronic hepatitis C, 2 days after starting pegIFN/ribavirin therapy, a stronger ISG15 inducibility correlates with a milder Treg depletion. Ex vivo, in systemic lupus erythematosus patients, higher levels of ISG15 are associated to reduced STAT1 phosphorylation in response to IFNα, and also to increased frequencies of Tregs, characterising active disease. CONCLUSION: Our results reveal a Treg-intrinsic role of ISG15 in dictating their refractoriness to the IFN signal, thus preserving the Treg population under inflammatory conditions.
RESUMEN
Neutrophils or PolyMorphonuclear Neutrophils (PMNs) are key effector cells of the innate immune system and thanks to their remarkable plasticity, establish a cross talk with T cells modulating their survival and effector functions. During Nonalcoholic Steatohepatitis (NASH), the advanced form of hepatic steatosis or NAFL, PMNs infiltrate liver tissue, becoming a histological feature of NASH. Our aim was to evaluate the frequency of PMNs in NAFL and NASH patients in order to understand how they modulate the activity of circulating CD4+ and CD8+ T cells. In our cohort of patients, NASH patients displayed a higher frequency of circulating PMNs that was strongly correlated to liver enzymes, grade of steatosis, inflammation and fibrosis, the hepatocellular ballooning, and NAFLD Activity Score (NAS). Furthermore, even if ex vivo, in both groups of patients, PMNs shared the same phenotype of resting cells, after 24 hours of coculture with autologous CD4+ and CD8+ T cells, PMNs of NASH patients acquired a more active phenotype, becoming able to strongly inhibit proliferation and activation of CD4+ and CD8+ T cells. The higher ability of PMNs of NASH patients in suppressing CD4+ and CD8+ T cells, over time, might contribute in reducing the immunological defense of liver tissue against damages thus taking part in the progression of the NAFL disease toward NASH.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Neutrófilos/inmunología , Enfermedad del Hígado Graso no Alcohólico/inmunología , Circulación Sanguínea , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Tolerancia Inmunológica , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Activación Neutrófila , Índice de Severidad de la EnfermedadRESUMEN
In this chapter, we discuss the role of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in the establishment of hepatocellular carcinoma (HCC), highlighting the key role of the multiple, non-mutually exclusive, pathways involved in the modulation of immune responses and in the orchestration of a chronic low-level inflammation state favouring HCC development. In particular, we discuss (i) HCC as a classical paradigm of inflammation-linked cancer; (ii) the role of the most relevant inflammatory cytokines involved (i.e. IL-6, TNF-α, IL-18, IL-1ß, TGF-ß IL-10); (iii) the role of T cell exhaustion by immune checkpoints; (iv) the role of the Wnt3a/ß-catenin signalling pathway and (v) the role of different subsets of suppressor cells.
Asunto(s)
Carcinoma Hepatocelular/virología , Virus de Hepatitis/patogenicidad , Inflamación/virología , Neoplasias Hepáticas/virología , Microambiente Tumoral , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Humanos , Inflamación/inmunología , Inflamación/patología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patologíaRESUMEN
In our study, we investigated the role of CD39 on tumor-infiltrating CD8+ T lymphocytes (CD8+ TILs) in colorectal, head and neck and pancreatic cancers. Partially confirming recent observations correlating the CD39 expression with T-cell exhaustion, we demonstrated a divergent functional activity in CD39+ CD8+ TILs. On the one hand, CD39+ CD8+ TILs (as compared to their CD39- counterparts) produced significantly lower IFN-γ and IL-2 amounts, expressed higher PD-1, and inversely correlated with perforin and granzyme B expression. On the other, they displayed a significantly higher proliferative capacity ex vivo that was inversely correlated with the PD-1 expression. Therefore, CD39+ CD8+ TILs, including those co-expressing the CD103 (a marker of T resident memory [TRM] cells), were defined as partially dysfunctional T cells that correlate with tumor patients with initial progression stages. Interestingly, our results identified for the first time a single nucleotide polymorphism (SNP rs10748643 A>G), as a genetic factor associated with CD39 expression in CD8+ TILs. Finally, we demonstrated that compounds inhibiting CD39-related ATPases improved CD39+ CD8+ T-cell effector function ex vivo, and that CD39+ CD8+ TILs displayed effective suppression function in vitro. Overall these data suggest that the SNP analysis may represent a suitable predictor of CD39+ CD8+ T-cell expression in cancer patients, and propose the modulation of CD39 as a new strategy to restore partially exhausted CD8+ TILs.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apirasa/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias/inmunología , Linfocitos T Citotóxicos/inmunología , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apirasa/antagonistas & inhibidores , Apirasa/genética , Células Cultivadas , Femenino , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Nivolumab/farmacología , Nivolumab/uso terapéutico , Polimorfismo de Nucleótido Simple , Cultivo Primario de Células , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/metabolismoRESUMEN
In this chapter, we summarize the latest findings in the field of immuno-oncology of women cancers, particularly ovarian and breast tumors. We describe the relationship between immune parameters and clinical outcomes by evaluating the contribution of different players of the tumor microenvironment, with a particular focus on different immune cell subsets and their essential role during the development of the disease, the response to standard chemotherapy, and to emerging immunotherapeutic approaches. By reviewing the molecular and genetic features of ovarian and breast cancer subtypes, we report on the multitude of factors influencing treatment outcome, with a particular interest on the possible influence of the immune system (i.e., tumor infiltrating lymphocytes, T cells, regulatory T cells, myeloid-derived suppressor cells, dendritic cells, macrophages, B cells, tumor-associated neutrophils). Finally, we discuss emerging immune targets and novel therapeutic modalities that are likely to profoundly influence clinical outcome and prognosis of breast and ovarian cancers in the next future.
Asunto(s)
Neoplasias de la Mama/inmunología , Linfocitos Infiltrantes de Tumor , Neoplasias Ováricas/inmunología , Microambiente Tumoral/inmunología , Linfocitos B , Células Dendríticas , Femenino , Humanos , Inmunoterapia , Macrófagos , Neutrófilos , Pronóstico , Linfocitos T ReguladoresRESUMEN
The mechanisms whereby autoreactive T cells escape peripheral tolerance establishing thus autoimmune diseases in humans remain an unresolved question. Here, we demonstrate that autoreactive polyfunctional CD8+ T cells recognizing self-antigens (i.e., vimentin, actin cytoplasmic 1, or non-muscle myosin heavy chain 9 epitopes) with high avidity, counter-regulate Tregs by killing them, in a consistent percentage of rheumatoid arthritis (RA) patients. Indeed, these CD8+ T cells express a phenotype and gene profile of effector (eff) cells and, upon antigen-specific activation, kill Tregs indirectly in an NKG2D-dependent bystander fashion in vitro. This data provides a mechanistic basis for the finding showing that AE-specific (CD107a+) CD8+ T killer cells correlate, directly with the disease activity score, and inversely with the percentage of activated Tregs, in both steady state and follow-up studies in vivo. In addition, multiplex immunofluorescence imaging analyses of inflamed synovial tissues in vivo show that a remarkable number of CD8+ T cells express granzyme-B and selectively contact FOXP3+ Tregs, some of which are in an apoptotic state, validating hence the possibility that CD8+ Teff cells can counteract neighboring Tregs within inflamed tissues, by killing them. Alternatively, the disease activity score of a different subset of patients is correlated with the expansion of a peculiar subpopulation of autoreactive low avidity, partially-activated (pa)CD8+ T cells that, despite they conserve the conventional naïve (N) phenotype, produce high levels of tumor necrosis factor (TNF)-α and exhibit a gene expression signature of a progressive activation state. Tregs directly correlate with the expansion of this autoreactive (low avidity) paCD8+ TN cell subset in vivo, and efficiently control their differentiation rather their proliferation in vitro. Interestingly, autoreactive high avidity CD8+ Teff cells or low avidity paCD8+ TN cells are significantly expanded in RA patients who would become non-responders or patients who would become responders to TNF-α inhibitor therapy, respectively. These data provide evidence of a previously undescribed role of such mechanisms in the progression and therapy of RA.
Asunto(s)
Artritis Reumatoide/inmunología , Autoinmunidad , Linfocitos T CD8-positivos/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/metabolismo , Biomarcadores , Linfocitos T CD8-positivos/metabolismo , Susceptibilidad a Enfermedades , Femenino , Antígenos de Histocompatibilidad Clase I/química , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Inmunomodulación , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Especificidad del Receptor de Antígeno de Linfocitos T , Linfocitos T Reguladores/metabolismoRESUMEN
In this study, we investigated the role of the Wnt/ß-catenin signaling pathway in antitumor immune responses. We report that the concentration of secreted Wnt3a was significantly higher in conditioned medium from tumor or nontumor tissues obtained from all hepatocellular carcinoma or colorectal cancer patients tested, than in serum of healthy donors or patients. In addition, both Wnt3a and ß-catenin were overexpressed by tumor-infiltrating and nontumor-infiltrating CD4+ or CD8+ T cells. The majority of these T cells expressed a dysfunctional effector memory Eomes+T-bet-phenotype that we defined as partially exhausted, because they performed effector functions (in terms of interferon-γ and tumor necrosis factor-α production, as well as CD107a mobilization) despite their PD-1 expression. Wnt3a/ß-catenin signaling in T naïve cells in vitro recapitulated the T-cell setting in vivo Indeed, the differentiation of cultured T naïve cells was arrested, producing cells that resembled the EomeshighT-betlowß-cateninhigh T cells with moderate effector functions that infiltrated tumor and nontumor areas. Wnt3a blockade improved the capacity of T naïve cells to differentiate into effector cells in vitro However, Wnt3a blockade did not affect the function and phenotype of differentiated, partially exhausted, tumor-infiltrating T cells ex vivo Taken together, our data suggest that Wnt3a blockade halts the capacity of Wnt/ß-catenin signaling to inhibit the differentiation of T naïve cells, but it does not restore the dysfunction of differentiated T cells, in the tumor setting. Cancer Immunol Res; 6(8); 941-52. ©2018 AACR.
Asunto(s)
Carcinoma Hepatocelular/inmunología , Neoplasias Colorrectales/inmunología , Neoplasias Hepáticas/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Vía de Señalización Wnt/inmunología , Anciano , Anciano de 80 o más Años , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Femenino , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Proteína Wnt3A/inmunología , beta Catenina/metabolismoRESUMEN
The tumor microenvironment restrains conventional T cell (Tconv) activation while facilitating the expansion of Tregs. Here we showed that Tregs' advantage in the tumor milieu relies on supplemental energetic routes involving lipid metabolism. In murine models, tumor-infiltrating Tregs displayed intracellular lipid accumulation, which was attributable to an increased rate of fatty acid (FA) synthesis. Since the relative advantage in glucose uptake may fuel FA synthesis in intratumoral Tregs, we demonstrated that both glycolytic and oxidative metabolism contribute to Tregs' expansion. We corroborated our data in human tumors showing that Tregs displayed a gene signature oriented toward glycolysis and lipid synthesis. Our data support a model in which signals from the tumor microenvironment induce a circuitry of glycolysis, FA synthesis, and oxidation that confers a preferential proliferative advantage to Tregs, whose targeting might represent a strategy for cancer treatment.
Asunto(s)
Ácidos Grasos/inmunología , Glucólisis/inmunología , Neoplasias Experimentales/inmunología , Linfocitos T Reguladores/inmunología , Microambiente Tumoral/inmunología , Animales , Línea Celular Tumoral , Acido Graso Sintasa Tipo I/genética , Acido Graso Sintasa Tipo I/inmunología , Ácidos Grasos/genética , Humanos , Ratones , Ratones Transgénicos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Oxidación-Reducción , Linfocitos T Reguladores/patología , Microambiente Tumoral/genéticaRESUMEN
IL-18 is an inflammasome-related cytokine, member of the IL-1 family, produced by a wide range of cells in response to signals by several pathogen- or damage-associated molecular patterns. It can be highly represented in tumor patients, but its relevance in human cancer development is not clear. In this study, we provide evidence that IL-18 is principally expressed in tumor cells and, in concert with other conventional Th1 cell-driven cytokines, has a pivotal role in establishing a pro-inflammatory milieu in the tumor microenvironment of human non-small cell lung cancer (NSCLC). Interestingly, the analysis of tumor-infiltrating CD8+ T cell populations showed that (i) the relative IL-18 receptor (IL-18R) is significantly more expressed by the minority of cells with a functional phenotype (T-bet+Eomes+), than by the majority of those with the dysfunctional phenotype T-bet-Eomes+ generally resident within tumors; (ii) as a consequence, the former are significantly more responsive than the latter to IL-18 stimulus in terms of IFNγ production ex vivo; (iii) PD-1 expression does not discriminate these two populations. These data indicate that IL-18R may represent a biomarker of the minority of functional tumor-infiltrating CD8+ T cells in adenocarcinoma NSCLC patients. In addition, our results lead to envisage the possible therapeutic usage of IL-18 in NSCLC, even in combination with other checkpoint inhibitor approaches.
RESUMEN
Regulatory T cells (Tregs) are defined as immunosuppressive cells playing crucial roles in the establishment and maintenance of immune homeostasis. During the course of immune responses, Tregs control the balance between host defense from pathogens and the prevention of excessive immunity. Here, we describe the phenotypic analysis of Tregs, evaluated in peripheral blood mononuclear cells of healthy adults, by multiparameter flow cytometry, which allows examining the expression of peculiar markers of Treg subpopulations with different features, and provides efficient discrimination of multiple characteristics at the single-cell level. The same technique may be applied to characterize mononuclear cells extracted from different specimens, including whole blood, biological fluids or solid tissues. The immunoregulatory identity of a certain Treg subpopulation may be functionally verified by performing an in vitro suppression assay described here, testing the capability of Tregs to suppress the activation of responder cells.
Asunto(s)
Citometría de Flujo/métodos , Análisis de la Célula Individual/métodos , Linfocitos T Reguladores/inmunología , Proliferación Celular/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunosupresores/uso terapéutico , Leucocitos Mononucleares/inmunologíaRESUMEN
Tregs can contribute to tumor progression by suppressing antitumor immunity. Exceptionally, in human colorectal cancer (CRC), Tregs are thought to exert beneficial roles in controlling pro-tumor chronic inflammation. The goal of our study was to characterize CRC-infiltrating Tregs at multiple levels, by phenotypical, molecular and functional evaluation of Tregs from the tumor site, compared to non-tumoral mucosa and peripheral blood of CRC patients. The frequency of Tregs was higher in mucosa than in blood, and further significantly increased in tumor. Ex vivo, those Tregs suppressed the proliferation of tumor-infiltrating CD8(+) and CD4(+) T cells. A differential compartmentalization was detected between Helios(high) and Helios(low) Treg subsets (thymus-derived versus peripherally induced): while Helios(low) Tregs were enriched in both sites, only Helios(high) Tregs accumulated significantly and specifically in tumors, displayed a highly demethylated TSDR region and contained high proportions of cells expressing CD39 and OX40, markers of activation and suppression. Besides the suppression of T cells, Tregs may contribute to CRC progression also through releasing IL-17, or differentiating into Tfr cells that potentially antagonize a protective Tfh response, events that were both detected in tumor-associated Tregs. Overall, our data indicate that Treg accumulation may contribute through multiple mechanisms to CRC establishment and progression.
RESUMEN
Type I IFNs are pleiotropic cytokines that exert concerted activities in the development of antiviral responses. Regulatory T cells represent a physiologic checkpoint in the balance between immunity and tolerance, requiring fine and rapid controls. Here, we show that human regulatory T cells are particularly sensitive to the sequential effects of IFN-α. First, IFN-α exerts a rapid, antiproliferative and proapoptotic effect in vitro and in vivo, as early as after 2 d of pegylated IFN/ribavirin therapy in patients with chronic hepatitis C. Such activities result in the decline, at d 2, in circulating regulatory T cell frequency and specifically of the activated regulatory T cell subset. Later, IFN-based therapy restrains the fraction of regulatory T cells that can be polarized into IFN-γ-producing Th1-like regulatory T cells known to contribute to chronic immune activation in type 1 inflammation. Indeed, Th1-like regulatory T cell frequency significantly declines after 30 d of therapy in vivo in relation to the persistent decline of relevant IL-12 sources, namely, myeloid and 6-sulfo LacNAc-expressing dendritic cells. This event is recapitulated by experiments in vitro, providing evidence that it may be attributable to the inhibitory effect of IFN-α on IL-12-induced, Th1-like regulatory T cell polarization. In summary, our results suggest that IFN-α-driven, early regulatory T cell depletion contributes to the development of antiviral immunity, ultimately resulting in the resolution of type 1 inflammation.
Asunto(s)
Hepatitis C Crónica/inmunología , Interferón-alfa/farmacología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Células TH1/inmunología , Adolescente , Adulto , Anciano , Antivirales/farmacología , Citocinas/metabolismo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Femenino , Hepacivirus/inmunología , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Humanos , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Subgrupos de Linfocitos T/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Células TH1/efectos de los fármacosRESUMEN
Regulatory T cells (Treg) exert a dominant role in the protection of unwanted immune responses and in the resolution of inflammation. To ensure the proper mounting of protective immune responses, Treg should be finely modulated by microenvironmental signals, mostly conveyed by cytokines. Type-I interferons are pleiotropic cytokines, best known for their anti-viral activities but also playing relevant immunostimulatory as well as immunomodulatory functions. The impact of type-I interferons on Treg homeostasis and functions is quite controversial, as some studies indicate that interferons sustain Treg stability and suppression, while other reports describe a null or even negative role for interferons in Treg activities. Interferons may also establish alternative routes of suppression, through the induction of other suppressive populations, such as Tr1 and the recently discovered FoxA1+ Treg. Discrepant results about Treg behavior in vivo emerge also from data collected in patients with multiple sclerosis, chronic hepatitis C or cancer undergoing interferon therapy. Concurrent events, such as Treg-extrinsic interferon activities, desensitization to chronic interferon exposure, and changes in microenvironmental signals during the evolution of diseases, may contribute to depict such a complex scenario, in which short-term and long-term effects of interferon exposure may give rise to apparently opposite conclusions.
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Inmunomodulación , Interferón Tipo I/inmunología , Linfocitos T Reguladores/inmunología , Citocinas/inmunología , Hepatitis C/terapia , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/inmunología , Humanos , Tolerancia Inmunológica , Inflamación , Interferón Tipo I/metabolismo , Interferones/inmunología , Activación de Linfocitos , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/terapia , Transducción de SeñalRESUMEN
Human regulatory T cells (Tregs) comprise an array of distinct subsets displaying diverse functions in response to microenvironmental signals. Here, we review our recent findings demonstrating the preferential accumulation of uncommitted, Th1-like and OX40- Tregs in non-cirrhotic tissues in contrast to the presence of committed, Th1-suppressing and OX40+ Tregs in cirrhotic and tumor contexts in human liver affected by chronic hepatitis C.