Respiratory complex I regulates dendritic cell maturation in explant model of human tumor immune microenvironment.
J Immunother Cancer
; 12(4)2024 Apr 11.
Article
em En
| MEDLINE
| ID: mdl-38604809
ABSTRACT
BACKGROUND:
Combining cytotoxic chemotherapy or novel anticancer drugs with T-cell modulators holds great promise in treating advanced cancers. However, the response varies depending on the tumor immune microenvironment (TIME). Therefore, there is a clear need for pharmacologically tractable models of the TIME to dissect its influence on mono- and combination treatment response at the individual level.METHODS:
Here we establish a patient-derived explant culture (PDEC) model of breast cancer, which retains the immune contexture of the primary tumor, recapitulating cytokine profiles and CD8+T cell cytotoxic activity.RESULTS:
We explored the immunomodulatory action of a synthetic lethal BCL2 inhibitor venetoclax+metformin drug combination ex vivo, discovering metformin cannot overcome the lymphocyte-depleting action of venetoclax. Instead, metformin promotes dendritic cell maturation through inhibition of mitochondrial complex I, increasing their capacity to co-stimulate CD4+T cells and thus facilitating antitumor immunity.CONCLUSIONS:
Our results establish PDECs as a feasible model to identify immunomodulatory functions of anticancer drugs in the context of patient-specific TIME.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sulfonamidas
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Neoplasias da Mama
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Compostos Bicíclicos Heterocíclicos com Pontes
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Metformina
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Antineoplásicos
Limite:
Female
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Humans
Idioma:
En
Revista:
J Immunother Cancer
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Finlândia