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1.
J Immunol ; 212(12): 1904-1912, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38668728

RESUMEN

NK cells have been shown to exhibit inflammatory and immunoregulatory functions in a variety of healthy and diseased settings. In the context of chronic viral infection and cancer, distinct NK cell populations that inhibit adaptive immune responses have been observed. To understand how these cells arise and further characterize their immunosuppressive role, we examined in vitro conditions that could polarize human NK cells into an inhibitory subset. TGF-ß1 has been shown to induce regulatory T cells in vitro and in vivo; we therefore investigated if TGF-ß1 could also induce immunosuppressive NK-like cells. First, we found that TGF-ß1/IL-15, but not IL-15 alone, induced CD103+CD49a+ NK-like cells from peripheral blood NK cells, which expressed markers previously associated with inhibitory CD56+ innate lymphoid cells, including high expression of GITR and CD101. Moreover, supernatant from ascites collected from patients with ovarian carcinoma also induced CD103+CD49a+ NK-like cells in vitro in a TGF-ß-dependent manner. Interestingly, TGF-ß1/IL-15-induced CD103+CD56+ NK-like cells suppressed autologous CD4+ T cells in vitro by reducing absolute number, proliferation, and expression of activation marker CD25. Collectively, these findings provide new insight into how NK cells may acquire an inhibitory phenotype in TGF-ß1-rich environments.


Asunto(s)
Interleucina-15 , Células Asesinas Naturales , Factor de Crecimiento Transformador beta1 , Humanos , Células Asesinas Naturales/inmunología , Interleucina-15/inmunología , Interleucina-15/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Femenino , Antígenos CD/metabolismo , Antígenos CD/inmunología , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/patología , Cadenas alfa de Integrinas/metabolismo , Cadenas alfa de Integrinas/inmunología , Antígeno CD56/metabolismo , Células Cultivadas , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Activación de Linfocitos/inmunología
2.
Nat Commun ; 15(1): 1094, 2024 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-38321065

RESUMEN

Immunotherapies targeting PD-1/PD-L1 are now widely used in the clinic to treat a variety of malignancies. While most of the research on T cell exhaustion and PD-1 blockade has been focused on conventional αß T cells, the contribution of innate-like T cells such as γδ T cells to anti-PD-1/PD-L1 mediated therapy is limited. Here we show that tumor reactive γδ T cells respond to PD-1 blockade in a Merkel cell carcinoma (MCC) patient experiencing a complete response to therapy. We find clonally expanded γδ T cells in the blood and tumor after pembrolizumab treatment, and this Vγ2Vδ1 clonotype recognizes Merkel cancer cells in a TCR-dependent manner. Notably, the intra-tumoral γδ T cells in the MCC patient are characterized by higher expression of PD-1 and TIGIT, relative to conventional CD4 and CD8 T cells. Our results demonstrate that innate-like T cells could also contribute to an anti-tumor response after PD-1 blockade.


Asunto(s)
Carcinoma de Células de Merkel , Neoplasias Cutáneas , Humanos , Receptor de Muerte Celular Programada 1/metabolismo , Antígeno B7-H1 , Linfocitos T CD8-positivos/metabolismo , Neoplasias Cutáneas/patología
3.
Cancer Immunol Res ; 10(4): 437-452, 2022 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-35181779

RESUMEN

Regulatory T cells (Treg) are an integral component of the adaptive immune system that negatively affect antitumor immunity. Here, we investigated the role of the E3 ubiquitin ligase casitas B-lineage lymphoma-b (Cbl-b) in establishing CD8+ T-cell resistance to Treg-mediated suppression to enhance antitumor immunity. Transcriptomic analyses suggested that Cbl-b regulates pathways associated with cytokine signaling and cellular proliferation. We showed that the hypersecretion of IFNγ by Cbl-b-deficient CD8+ T cells selectively attenuated CD8+ T-cell suppression by Tregs. Although IFNγ production by Cbl-b-deficient T cells contributed to phenotypic alterations in Tregs, the cytokine did not attenuate the suppressive function of Tregs. Instead, IFNγ had a profound effect on CD8+ T cells by directly upregulating interferon-stimulated genes and modulating T-cell activation. In murine models of adoptive T-cell therapy, Cbl-b-deficient T cells elicited superior antitumor immune response. Furthermore, Cbl-b-deficient CD8+ T cells were less susceptible to suppression by Tregs in the tumor through the effects of IFNγ. Collectively, this study demonstrates that the hypersecretion of IFNγ serves as a key mechanism by which Cbl-b-deficient CD8+ T cells are rendered resistant to Tregs. See related Spotlight by Wolf and Baier, p. 370.


Asunto(s)
Linfocitos T Reguladores , Proteínas Adaptadoras Transductoras de Señales , Animales , Linfocitos T CD8-positivos , Interferón gamma/metabolismo , Ratones , Proteínas Proto-Oncogénicas c-cbl/genética , Proteínas Proto-Oncogénicas c-cbl/metabolismo
4.
Cell Metab ; 33(12): 2415-2427.e6, 2021 12 07.
Artículo en Inglés | MEDLINE | ID: mdl-34879240

RESUMEN

Metabolic programming is intricately linked to the anti-tumor properties of T cells. To study the metabolic pathways associated with increased anti-tumor T cell function, we utilized a metabolomics approach to characterize three different CD8+ T cell subsets with varying degrees of anti-tumor activity in murine models, of which IL-22-producing Tc22 cells displayed the most robust anti-tumor activity. Tc22s demonstrated upregulation of the pantothenate/coenzyme A (CoA) pathway and a requirement for oxidative phosphorylation (OXPHOS) for differentiation. Exogenous administration of CoA reprogrammed T cells to increase OXPHOS and adopt the CD8+ Tc22 phenotype independent of polarizing conditions via the transcription factors HIF-1α and the aryl hydrocarbon receptor (AhR). In murine tumor models, treatment of mice with the CoA precursor pantothenate enhanced the efficacy of anti-PDL1 antibody therapy. In patients with melanoma, pre-treatment plasma pantothenic acid levels were positively correlated with the response to anti-PD1 therapy. Collectively, our data demonstrate that pantothenate and its metabolite CoA drive T cell polarization, bioenergetics, and anti-tumor immunity.


Asunto(s)
Coenzima A , Subgrupos de Linfocitos T , Animales , Linfocitos T CD8-positivos , Diferenciación Celular , Coenzima A/metabolismo , Humanos , Activación de Linfocitos , Ratones , Subgrupos de Linfocitos T/metabolismo
5.
Cancer Immunol Res ; 8(3): 321-333, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31964625

RESUMEN

CD8+ T cells can be polarized into several different subsets as defined by the cytokines they produce and the transcription factors that govern their differentiation. Here, we identified the polarizing conditions to induce an IL22-producing CD8+ Tc22 subset, which is dependent on IL6 and the aryl hydrocarbon receptor transcription factor. Further characterization showed that this subset was highly cytolytic and expressed a distinct cytokine profile and transcriptome relative to other subsets. In addition, polarized Tc22 were able to control tumor growth as well as, if not better than, the traditional IFNγ-producing Tc1 subset. Tc22s were also found to infiltrate the tumors of human patients with ovarian cancer, comprising up to approximately 30% of expanded CD8+ tumor-infiltrating lymphocytes (TIL). Importantly, IL22 production in these CD8+ TILs correlated with improved recurrence-free survival. Given the antitumor properties of Tc22 cells, it may be prudent to polarize T cells to the Tc22 lineage when using chimeric antigen receptor (CAR)-T or T-cell receptor (TCR) transduction-based immunotherapies.


Asunto(s)
Inmunoterapia Adoptiva/métodos , Interleucina-6/farmacología , Interleucinas/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Ováricas/terapia , Subgrupos de Linfocitos T/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/inmunología , Polaridad Celular/inmunología , Femenino , Humanos , Interleucina-6/biosíntesis , Interleucina-6/genética , Interleucina-6/inmunología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Melanoma Experimental/genética , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Melanoma Experimental/terapia , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neoplasias Ováricas/genética , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/patología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Hidrocarburo de Aril/inmunología , Proteínas de Dominio T Box/inmunología , Subgrupos de Linfocitos T/efectos de los fármacos , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/inmunología , Transcriptoma , Células Tumorales Cultivadas , Interleucina-22
6.
Cancer Res ; 79(3): 445-451, 2019 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-30573521

RESUMEN

Memory CD8+ T cells (Tmem) are superior mediators of adoptive cell therapy (ACT) compared with effector CD8+ T cells (Teff) due to increased persistence in vivo. Underpinning Tmem survival is a shift in cellular metabolism away from aerobic glycolysis towards fatty acid oxidation (FAO). Here we investigated the impact of the peroxisome proliferator-activated receptor (PPAR) agonist GW501516 (GW), an agent known to boost FAO in other tissues, on CD8+ T-cell metabolism, function, and efficacy in a murine ACT model. Via activation of both PPARα and PPARδ/ß, GW treatment increased expression of carnitine palmitoyl transferase 1a, the rate-limiting enzyme of FAO, in activated CD8+ T cells. Using a metabolomics approach, we demonstrated that GW increased the abundance of multiple different acylcarnitines, consistent with enhanced FAO. T cells activated in the presence of GW and inflammatory signals, either mature dendritic cells or IL12, also demonstrated enhanced production of IFNγ and expression of T-bet. Despite high expression of T-bet, a characteristic of short-lived effector cells, GW-treated cells demonstrated enhanced persistence in vivo and superior efficacy in a model of ACT. Collectively, these data identify combined PPARα and PPARδ/ß agonists as attractive candidates for further studies and rapid translation into clinical trials of ACT. SIGNIFICANCE: Dual activation of peroxisome proliferator-activated receptors α and δ improves the efficacy of adoptive cell therapy by reprogramming T-cell metabolism and cytokine expression.


Asunto(s)
Inmunoterapia Adoptiva , Inflamación/genética , Neoplasias/genética , PPAR alfa/genética , PPAR delta/genética , Animales , Linfocitos T CD8-positivos/inmunología , Ácidos Grasos/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Inflamación/inmunología , Inflamación/patología , Inflamación/terapia , Interferón gamma/genética , Interleucina-12/genética , Interleucina-12/inmunología , Metabolismo de los Lípidos/genética , Ratones , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapia , Oxidación-Reducción , PPAR alfa/agonistas , PPAR delta/agonistas , PPAR-beta/agonistas , PPAR-beta/genética , Tiazoles/uso terapéutico
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