Sammanfattning
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.Data are available upon reasonable request.
Originalspråk | engelska |
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Artikelnummer | e008053 |
Tidskrift | Journal for ImmunoTherapy of Cancer |
Volym | 12 |
Nummer | 4 |
Antal sidor | 18 |
ISSN | 2051-1426 |
DOI | |
Status | Publicerad - 2024 |
MoE-publikationstyp | A1 Tidskriftsartikel-refererad |
Vetenskapsgrenar
- 3122 Cancersjukdomar