Mutant p53 controls tumour microenvironment via extracellular vesicles

Background: TP53 mutants (mutp53) are involved in the pathogenesis of most human cancers. Specific mutp53 proteins gain oncogenic functions (GOF) distinct from the tumour suppressor activity of the wildtype protein. Tumour-associated-macrophages (TAM), a hallmark of solid tumours, are typically correlated with poor prognosis. We investigated cell-to-cell communication between cancer cells harboring mutp53 GOF and neighboring macrophages. Methods: Primary human macrophages were co-cultured with colon carcinoma cell lines differing by their p53 status in a transwell system. We identified inflammatory and pro-tumoural phenotypes of co-cultured macrophages using qPCR, ELISA and various functional biological assays. Co-injection of macrophages and tumour cells in NOD-SCID mice was used to determine tumour-supportive characteristics using both xenografts and orthotopic models. Resected colon tumours from colorectal cancer patients were genotyped, divided into groups of wt vs. mutant p53 and analysed for the correlation with tumour-associated macrophages and survival. Results: We report a non-cell-autonomous mechanism whereby human mutp53 cancer cells reprogram macrophages to a tumour supportive and anti-inflammatory state. The colon carcinoma cells harbouring GOF mutp53 selectively shed miR-1246-enriched exosomes. Uptake of these exosomes by neighbouring macrophages triggers their miR-1246-dependent reprogramming into a cancer-promoting state. Mutp53-reprogammed TAM favours anti-inflammatory immunosuppression with increased activity of TGF-ß. These findings, associated with poor survival in colon cancer patients, strongly support a microenvironmental GOF role for mutp53 in actively engaging the immune system to promote cancer progression and metastasis. Summary/conclusion: Genetic alterations in the tumour might exacerbate tumourigenesis mediated by extracellular vesicles transferred between tumour cells and associated macrophages. The transfer of miR-1246 shapes a tumour supporting microenvironment that could be targeted in the future, using anti-miR therapies.