학술논문
Respiratory complex I regulates dendritic cell maturation in explant model of human tumor immune microenvironment.
Document Type
article
Author
Turpin, Rita; Liu, Ruixian; Munne, Pauliina; Peura, Aino; Rannikko, Jenna; Philips, Gino; Boeckx, Bram; Salmelin, Natasha; Hurskainen, Elina; Suleymanova, Ilida; Aung, July; Vuorinen, Elisa; Lehtinen, Laura; Mutka, Minna; Kovanen, Panu; Niinikoski, Laura; Meretoja, Tuomo; Mattson, Johanna; Mustjoki, Satu; Saavalainen, Päivi; Goga, Andrei; Lambrechts, Diether; Pouwels, Jeroen; Hollmén, Maija; Klefström, Juha
Source
Journal for ImmunoTherapy of Cancer. 12(4)
Subject
Language
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.