Respiratory Complex I Regulates Dendritic Cell Maturation in Explant Model of Human Tumor Immune Microenvironment

Abstract

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. 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. 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 anti-tumor immunity. Our results establish PDECs as a feasible model to identify immunomodulatory functions of anticancer drugs in the context of patient-specific TIME.

Respiratory complex I regulates dendritic cell maturation in explant model of human tumor immune microenvironment

“…Data can be found deposited online. 90 Mouse tissue spatial transcriptomics Two cryopreserved tumor tissue sections from one metformin-treated and one untreated Wap-Myc mice were profiled for spatial transcriptomics using the 10x Genomics Visium spatial RNA-sequencing technology with a resolution of 55 µm per spot. The tissues were cryosectioned at 10 µm thickness onto the Visium library preparation slide, fixed in methanol for 30 min, stained with Hematoxylin and Eosin Stain Kit (Vector Laboratories) and stored at −20°C until library preparation.…”

“…Data set found deposited online. 90 Multiplex and standard immunohistochemistry Tissues and explant cultures were fixed with 4% paraformaldehyde (PFA) and embedded in paraffin. The samples were sectioned into 5 µm slices and deparaffinized.…”