YKL-40 derived from infiltrating macrophages cooperates with GDF15 to establish an immune suppressive microenvironment in gallbladder cancer.
Cancer Lett
; 563: 216184, 2023 06 01.
Article
en En
| MEDLINE
| ID: mdl-37088328
ABSTRACT
Despite of the high lethality of gallbladder cancer (GBC), little is known regarding molecular regulation of the tumor immunosuppressive microenvironment. Here, we determined tumor expression levels of YKL-40 and the molecular mechanisms by which YKL-40 regulates escape of anti-tumor immune surveillance. We found that elevated expression levels of YKL-40 in plasma and tissue were correlated with tumor size, stage IV and lymph node metastasis. Single cell transcriptome analysis revealed that YKL-40 was predominantly derived from M2-like subtype of infiltrating macrophages. Blockade of M2-like macrophage differentiation of THP-1 cells with YKL-40 shRNA resulted in reprogramming to M1-like macrophages and restricting tumor development. YKL-40 induced tumor cell expression and secretion of growth differentiation factor 15 (GDF15), thus coordinating to promote PD-L1 expression mediated by PI3K, AKT and/or Erk activation. Interestingly, extracellular GDF15 inhibited intracellular expression of GDF15 that suppressed PD-L1 expression. Thus, YKL-40 disrupted the balance of pro- and anti-PD-L1 regulation to enhance expression of PD-L1 and inhibition of T cell cytotoxicity, leading to tumor immune evasion. The data suggest that YKL-40 and GDF15 could serve as diagnostic biomarkers and immunotherapeutic targets for GBC.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias de la Vesícula Biliar
Límite:
Humans
Idioma:
En
Revista:
Cancer Lett
Año:
2023
Tipo del documento:
Article
País de afiliación:
China