免疫系统
肿瘤微环境
外植体培养
癌症研究
树突状细胞
医学
免疫学
生物
体外
生物化学
作者
Rita Turpin,Ruixian Liu,Pauliina Munne,Aino Peura,Jenna H. Rannikko,Gino Philips,Bram Boeckx,Natasha Salmelin,Elina Hurskainen,Ilida Suleymanova,July Aung,Elisa M. Vuorinen,Laura Lehtinen,Minna Mutka,Panu E. Kovanen,Laura Niinikoski,Tuomo J Meretoja,Johanna Mattson,Satu Mustjoki,Päivi Saavalainen
标识
DOI:10.1136/jitc-2023-008053
摘要
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.
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