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1.
Nat Immunol ; 22(3): 358-369, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33432230

RESUMEN

CD8+ T cell exhaustion dampens antitumor immunity. Although several transcription factors have been identified that regulate T cell exhaustion, the molecular mechanisms by which CD8+ T cells are triggered to enter an exhausted state remain unclear. Here, we show that interleukin-2 (IL-2) acts as an environmental cue to induce CD8+ T cell exhaustion within tumor microenvironments. We find that a continuously high level of IL-2 leads to the persistent activation of STAT5 in CD8+ T cells, which in turn induces strong expression of tryptophan hydroxylase 1, thus catalyzing the conversion to tryptophan to 5-hydroxytryptophan (5-HTP). 5-HTP subsequently activates AhR nuclear translocation, causing a coordinated upregulation of inhibitory receptors and downregulation of cytokine and effector-molecule production, thereby rendering T cells dysfunctional in the tumor microenvironment. This molecular pathway is not only present in mouse tumor models but is also observed in people with cancer, identifying IL-2 as a novel inducer of T cell exhaustion.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Interleucina-2/metabolismo , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Neoplasias/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Microambiente Tumoral , 5-Hidroxitriptófano/metabolismo , Animales , Anticuerpos Neutralizantes/farmacología , Antineoplásicos/farmacología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/deficiencia , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Células HEK293 , Humanos , Interleucina-2/antagonistas & inhibidores , Interleucina-2/genética , Células Jurkat , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Células MCF-7 , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/inmunología , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Células 3T3 NIH , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/patología , Receptores de Hidrocarburo de Aril/deficiencia , Receptores de Hidrocarburo de Aril/genética , Transducción de Señal , Triptófano Hidroxilasa/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
2.
iScience ; 25(5): 104347, 2022 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-35602958

RESUMEN

Exhausted CD8+ T cells with limited effector functions and high expression of multiple co-inhibitory receptors are one of the main barriers hindering antitumor immunity. The NADase CD38 has received considerable attention as a biomarker of CD8+ T cell exhaustion, but it remains unclear whether the increased CD38 directly promotes T cell dysfunctionality. Here, we surprisingly found that although Cd38 deficiency partially reverses NAD+ degradation and T cell dysfunction in vitro, the terminal exhausted differentiation of adoptively transferred CD8+ T cells in tumor is not impacted by either deficiency or overexpression of CD38. Monitoring the dynamic NAD+ levels shows that NAD+ levels are comparable between tumor infiltrated WT and Cd38 -/- OT-1 cells. Therefore, our results suggest that decreased NAD+ are correlated with T cell dysfunction, but deficiency of CD38 is not enough for rescuing NAD+ in tumor infiltrated CD8+ T cells and fails to increase the efficacy of antitumor T cell therapy.

3.
Cell Death Dis ; 12(7): 680, 2021 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-34226519

RESUMEN

It has been recently reported that CD38 expressed on tumor cells of multiple murine and human origins could be upregulated in response to PD-L1 antibody therapy, which led to dysfunction of tumor-infiltrating CD8+ T immune cells due to increasing the production of adenosine. However, the role of tumor expressed-CD38 on neoplastic formation and progression remains elusive. In the present study, we aimed to delineate the molecular and biochemical function of the tumor-associated CD38 in lung adenocarcinoma progression. Our clinical data showed that the upregulation of tumor-originated CD38 was correlated with poor survival of lung cancer patients. Using multiple in vitro assays we found that the enzymatic activity of tumor expressed-CD38 facilitated lung cancer cell migration, proliferation, colony formation, and tumor development. Consistently, our in vivo results showed that inhibition of the enzymatic activity or antagonizing the enzymatic product of CD38 resulted in the similar inhibition of tumor proliferation and metastasis as CD38 gene knock-out or mutation. At biochemical level, we further identified that cADPR, the mainly hydrolytic product of CD38, was responsible for inducing the opening of TRPM2 iron channel leading to the influx of intracellular Ca2+ and then led to increasing levels of NRF2 while decreasing expression of KEAP1 in lung cancer cells. These findings suggested that malignant lung cancer cells were capable of using cADPR catalyzed by CD38 to facilitate tumor progression, and blocking the enzymatic activity of CD38 could be represented as an important strategy for preventing tumor progression.


Asunto(s)
ADP-Ribosil Ciclasa 1/metabolismo , Adenocarcinoma del Pulmón/enzimología , ADP-Ribosa Cíclica/metabolismo , Neoplasias Pulmonares/enzimología , Glicoproteínas de Membrana/metabolismo , Células A549 , ADP-Ribosil Ciclasa 1/genética , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/secundario , Animales , Señalización del Calcio , Carcinoma Pulmonar de Lewis/enzimología , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/patología , Movimiento Celular , Proliferación Celular , Bases de Datos Genéticas , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Glicoproteínas de Membrana/genética , Ratones Endogámicos C57BL , Persona de Mediana Edad , Factor 2 Relacionado con NF-E2/metabolismo , Invasividad Neoplásica , Canales Catiónicos TRPM/metabolismo
4.
Cancer Cell ; 33(3): 480-494.e7, 2018 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-29533786

RESUMEN

Despite the clinical successes fostered by immune checkpoint inhibitors, mechanisms underlying PD-1 upregulation in tumor-infiltrating T cells remain an enigma. Here, we show that tumor-repopulating cells (TRCs) drive PD-1 upregulation in CD8+ T cells through a transcellular kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) pathway. Interferon-γ produced by CD8+ T cells stimulates release of high levels of Kyn produced by TRCs, which is transferred into adjacent CD8+ T cells via the transporters SLC7A8 and PAT4. Kyn induces and activates AhR and thereby upregulates PD-1 expression. This Kyn-AhR pathway is confirmed in both tumor-bearing mice and cancer patients and its blockade enhances antitumor adoptive T cell therapy efficacy. Thus, we uncovered a mechanism of PD-1 upregulation with potential tumor immunotherapeutic applications.


Asunto(s)
Linfocitos T CD8-positivos/efectos de los fármacos , Quinurenina/farmacología , Receptor de Muerte Celular Programada 1/efectos de los fármacos , Receptores de Hidrocarburo de Aril/efectos de los fármacos , Animales , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Humanos , Interferón gamma/inmunología , Ratones , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología
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