CD103+ regulatory T cells underlie resistance to radio-immunotherapy and impair CD8+ T cell activation in glioblastoma.
Nat Cancer
; 4(5): 665-681, 2023 05.
Article
em En
| MEDLINE
| ID: mdl-37081259
ABSTRACT
Glioblastomas are aggressive primary brain tumors with an inherent resistance to T cell-centric immunotherapy due to their low mutational burden and immunosuppressive tumor microenvironment. Here we report that fractionated radiotherapy of preclinical glioblastoma models induce a tenfold increase in T cell content. Orthogonally, spatial imaging mass cytometry shows T cell enrichment in human recurrent tumors compared with matched primary glioblastoma. In glioblastoma-bearing mice, α-PD-1 treatment applied at the peak of T cell infiltration post-radiotherapy results in a modest survival benefit compared with concurrent α-PD-1 administration. Following α-PD-1 therapy, CD103+ regulatory T cells (Tregs) with upregulated lipid metabolism accumulate in the tumor microenvironment, and restrain immune checkpoint blockade response by repressing CD8+ T cell activation. Treg targeting elicits tertiary lymphoid structure formation, enhances CD4+ and CD8+ T cell frequency and function and unleashes radio-immunotherapeutic efficacy. These results support the rational design of therapeutic regimens limiting the induction of immunosuppressive feedback pathways in the context of T cell immunotherapy in glioblastoma.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Glioblastoma
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Cancer
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Holanda