B-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by IL-12.
Sci Rep
; 12(1): 11870, 2022 07 13.
Article
en En
| MEDLINE
| ID: mdl-35831470
ABSTRACT
Immunotherapies have revolutionized the treatment of B-cell acute lymphoblastic leukemia (B-ALL), but the duration of responses is still sub-optimal. We sought to identify mechanisms of immune suppression in B-ALL and strategies to overcome them. Plasma collected from children with B-ALL with measurable residual disease after induction chemotherapy showed differential cytokine expression, particularly IL-7, while single-cell RNA-sequencing revealed the expression of genes associated with immune exhaustion in immune cell subsets. We also found that the supernatant of leukemia cells suppressed T-cell function ex vivo. Modeling B-ALL in mice, we observed an altered tumor immune microenvironment, including compromised activation of T-cells and dendritic cells (DC). However, recombinant IL-12 (rIL-12) treatment of mice with B-ALL restored the levels of several pro-inflammatory cytokines and chemokines in the bone marrow and increased the number of splenic and bone marrow resident T-cells and DCs. RNA-sequencing of T-cells isolated from vehicle and rIL-12 treated mice with B-ALL revealed that the leukemia-induced increase in genes associated with exhaustion, including Lag3, Tigit, and Il10, was abrogated with rIL-12 treatment. In addition, the cytolytic capacity of T-cells co-cultured with B-ALL cells was enhanced when IL-12 and blinatumomab treatments were combined. Overall, these results demonstrate that the leukemia immune suppressive microenvironment can be restored with rIL-12 treatment which has direct therapeutic implications.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Interleucina-12
/
Leucemia-Linfoma Linfoblástico de Células Precursoras
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Sci Rep
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos