Interruption of the intratumor CD8+ T cell:Treg crosstalk improves the efficacy of PD-1 immunotherapy.
Cancer Cell
; 42(6): 1051-1066.e7, 2024 Jun 10.
Article
em En
| MEDLINE
| ID: mdl-38861924
ABSTRACT
PD-1 blockade unleashes potent antitumor activity in CD8+ T cells but can also promote immunosuppressive T regulatory (Treg) cells, which may worsen the response to immunotherapy. Tumor-Treg inhibition is a promising strategy to improve the efficacy of checkpoint blockade immunotherapy; however, our understanding of the mechanisms supporting tumor-Tregs during PD-1 immunotherapy is incomplete. Here, we show that PD-1 blockade increases tumor-Tregs in mouse models of melanoma and metastatic melanoma patients. Mechanistically, Treg accumulation is not caused by Treg-intrinsic inhibition of PD-1 signaling but depends on an indirect effect of activated CD8+ T cells. CD8+ T cells produce IL-2 and colocalize with Tregs in mouse and human melanomas. IL-2 upregulates the anti-apoptotic protein ICOS on tumor-Tregs, promoting their accumulation. Inhibition of ICOS signaling before PD-1 immunotherapy improves control over immunogenic melanoma. Thus, interrupting the intratumor CD8+ T cellTreg crosstalk represents a strategy to enhance the therapeutic efficacy of PD-1 immunotherapy.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Interleucina-2
/
Linfócitos T Reguladores
/
Linfócitos T CD8-Positivos
/
Proteína Coestimuladora de Linfócitos T Induzíveis
/
Receptor de Morte Celular Programada 1
/
Inibidores de Checkpoint Imunológico
/
Imunoterapia
/
Melanoma
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article