The BTLA-HVEM axis restricts CAR T cell efficacy in cancer.
Nat Immunol
; 25(6): 1020-1032, 2024 Jun.
Article
in En
| MEDLINE
| ID: mdl-38831106
ABSTRACT
The efficacy of T cell-based immunotherapies is limited by immunosuppressive pressures in the tumor microenvironment. Here we show a predominant role for the interaction between BTLA on effector T cells and HVEM (TNFRSF14) on immunosuppressive tumor microenvironment cells, namely regulatory T cells. High BTLA expression in chimeric antigen receptor (CAR) T cells correlated with poor clinical response to treatment. Therefore, we deleted BTLA in CAR T cells and show improved tumor control and persistence in models of lymphoma and solid malignancies. Mechanistically, BTLA inhibits CAR T cells via recruitment of tyrosine phosphatases SHP-1 and SHP-2, upon trans engagement with HVEM. BTLA knockout thus promotes CAR signaling and subsequently enhances effector function. Overall, these data indicate that the BTLA-HVEM axis is a crucial immune checkpoint in CAR T cell immunotherapy and warrants the use of strategies to overcome this barrier.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Receptors, Immunologic
/
Immunotherapy, Adoptive
/
Receptors, Tumor Necrosis Factor, Member 14
/
Tumor Microenvironment
/
Receptors, Chimeric Antigen
Limits:
Animals
/
Humans
Language:
En
Journal:
Nat Immunol
Journal subject:
ALERGIA E IMUNOLOGIA
Year:
2024
Document type:
Article
Affiliation country: