A novel oral TLR7 agonist orchestrates immune response and synergizes with PD-L1 blockade via type I IFN pathway in lung cancer.
Int Immunopharmacol
; 137: 112478, 2024 Aug 20.
Article
em En
| MEDLINE
| ID: mdl-38901243
ABSTRACT
Despite the groundbreaking impact of immune checkpoint blockade (ICB), response rates in non-small cell lung cancer remain modest, particularly in immune-excluded or immune-desert microenvironments. Toll-like receptor 7 (TLR7) emerges as a latent target bridging innate and adaptive immunity, offering a promising avenue for combination therapies to augment ICB efficacy. Here, we explored the anti-tumor activity of the novel oral TLR7 agonist TQ-A3334 and its potential to enhance anti-programmed death ligand 1 (PD-L1) therapy through a combination strategy in a syngeneic murine lung cancer model. Oral administration of TQ-A3334 significantly alleviated tumor burden in C57BL/6J mice, modulated by type I interferon (IFN), and exhibited low toxicity. This therapy elicited activation of both innate and adaptive immune cells in tumor tissue, particularly increasing the abundance of CD8+ TILs through type I IFN pathway and subsequent CXCL10 expression. In vitro examinations validated that IFN-α-stimulated tumor cells exhibited increased secretion of CXCL10, conducive to the promoted trafficking of CD8+ T cells. Furthermore, combining TQ-A3334 with anti-PD-L1 treatment exceeded tumor control, with a further increase in CD8+ TIL frequency compared to monotherapy. These findings suggest that TQ-A3334 can mobilize innate immunity and promote T cell recruitment into the tumor microenvironment; a combination of TQ-A3334 and anti-PD-L1 antibodies can intensify the sensitivity of tumors to anti-PD-L1 therapy, which demonstrates significant potential for treating poorly immune-infiltrated lung cancer.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Interferon Tipo I
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Receptor 7 Toll-Like
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Antígeno B7-H1
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Inibidores de Checkpoint Imunológico
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Neoplasias Pulmonares
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Camundongos Endogâmicos C57BL
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article