RESUMEN
AML is the most common blood cancer in adults with a high relapse and an overall poor survival rate. NK cells have been demonstrated to have the capacity to eradicate AML blast, and an impaired NK cell function is involved in AML development and progression. Immune checkpoints are involved in immune escape in various cancers. Immune checkpoints blockade therapy mainly aimed to unleash CD8+T cells function, but NK cells have emerged as new target. However, immune checkpoints profile on NK cells has not been observed in AML patients. Here, we studied the immune checkpoints expression of NK cells from AML patients at initial diagnosis and found increased PD-1, TIGIT and TIM-3 expression compared to NK cells from healthy donors. Further analysis showed that TIGIT expressing NK cells from AML patients had a dysfunctional phenotype, as TIGIT+NK cells exhibit lower antileukemia effect, cytokine production and degranulation compared to TIGIT-NK cells. TIGIT blockade could significantly enhance the function of NK cells. Moreover, AML patients with high frequency of TIGIT+NK cells had higher frequency of poor prognosis risk. Further analysis found that IL-10 upregulated TIGIT expression on NK cells. Thus, TIGIT blockade alone or in combination with other therapy might be potential strategy to treat AML.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Proteínas de Punto de Control Inmunitario/metabolismo , Células Asesinas Naturales/inmunología , Leucemia Mieloide Aguda/patología , Recurrencia Local de Neoplasia/patología , Receptores Inmunológicos/metabolismo , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Citocinas , Femenino , Estudios de Seguimiento , Humanos , Proteínas de Punto de Control Inmunitario/genética , Células Asesinas Naturales/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/metabolismo , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/metabolismo , Fenotipo , Pronóstico , Receptores Inmunológicos/genética , Tasa de Supervivencia , Adulto JovenRESUMEN
Acute myeloid leukemia (AML) is one of the most common types of leukemia among adults with an overall poor prognosis and very limited treatment management. Immune checkpoint blockade of PD-1 alone or combined with other immune checkpoint blockade has gained impressive results in murine AML models by improving anti-leukemia CD8+T cell function, which has greatly promoted the strategy to utilize combined immune checkpoint inhibitors to treat AML patients. However, the expression profiles of these immune checkpoint receptors, such as co-inhibitory receptors PD-1 and TIGIT and co-stimulatory receptor CD226, in T cells from AML patients have not been clearly defined. Here we have defined subsets of CD8+ and CD4+ T cells in the peripheral blood (PB) from newly diagnosed AML patients and healthy controls (HCs). We have observed increased frequencies of PD-1- and TIGIT- expressing CD8+ T cells but decreased occurrence of CD226-expressing CD8+T cells in AML patients. Further analysis of these CD8+ T cells revealed a unique CD8+ T cell subset that expressed PD-1 and TIGIT but displayed lower levels of CD226 was associated with failure to achieve remission after induction chemotherapy and FLT3-ITD mutations which predict poor clinical prognosis in AML patients. Importantly, these PD-1+TIGIT+CD226-CD8+T cells are dysfunctional with lower expression of intracellular IFN-γ and TNF-α than their counterparts in HCs. Therefore, our studies revealed that an increased frequency of a unique CD8+ T cell subset, PD-1+TIGIT+CD226-CD8+T cells, is associated with CD8+T cell dysfunction and poor clinical prognosis of AML patients, which may reveal critical diagnostic or prognostic biomarkers and direct more efficient therapeutic strategies.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Citocinas/inmunología , Leucemia Mieloide/inmunología , Subgrupos de Linfocitos T/inmunología , Enfermedad Aguda , Adulto , Antígenos de Diferenciación de Linfocitos T/inmunología , Antígenos de Diferenciación de Linfocitos T/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Células Cultivadas , Citocinas/metabolismo , Femenino , Humanos , Quimioterapia de Inducción/métodos , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/genética , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
Acute myeloid leukemia (AML) is one of the most common types of blood cancer in adults and is associated with a poor survival rate. NK cells play a crucial role in combating AML, and alterations in immune checkpoint expression can impair NK cell function against AML. Targeting certain checkpoints may restore this function. CD96, an inhibitory immune checkpoint, has unclear expression and roles on NK cells in AML patients. In this study, we initially evaluated CD96 expression and compared CD96+ NK with the inhibitory receptor and stimulatory receptors on NK cells from AML patients at initial diagnosis. We observed increased CD96 expression on NK cells with dysfunctional phenotype. Further analysis revealed that CD96+ NK cells had lower IFN-γ production than CD96- NK cells. Blocking CD96 enhanced the cytotoxicity of primary NK and cord blood-derived NK (CB-NK) cells against leukemia cells. Notably, patients with a high frequency of CD96+ NK cells at initial diagnosis exhibited poorer clinical outcomes. Additionally, TGF-ß1 was found to enhance CD96 expression on NK cells via SMAD3 signaling. These findings suggest that CD96 is invovled in NK dysfunction against AML blast, and might be a potential target for restoring NK cell function in the fight against AML.