Tissue-specific imprinting shapes conventional dendritic cell functionality in tumors and non-malignant tissues

The tumor microenvironment (TME) is the intricate ecosystem of stromal, vascular and immune cells providing cellular and molecular cues for cancer development and escape from immunosurveillance. Therefore, exploring the heterogeneity and functional state of tumor infiltrating leukocytes has led to groundbreaking therapies aimed to unleash latent intratumor immunity. However, these therapies are effective for 'hot' tumors (high T-cell infiltration) but fail for 'cold' tumors, which exclude T cells. As such, converting cold tumors into hot is key to eradicate malignancies, yet it remains an unmet clinical need. In this complex scenario, dendritic cells (DCs) are instrumental to coordinate and initiate proficient antitumor T cell response through recruitment, (cross)-priming and co-stimulation. Nevertheless, while DC manipulation holds great potential for rescuing efficient anti-tumor immunity, clinical efforts have proven disappointing. With the aim of unraveling DCs’ adaptations within the TME, we performed an in- depth single cell integrated analysis across human tumors, delineating their functional states and tissue-specific plasticity. Here, we show that, comparing the transcriptome of cDC subsets in hot and cold tumors, cDC2s had the highest differentially expressed genes (DEGs), indicating strong TME influence. Specifically, in hot tumors, cDC2s exhibited upregulation of genes involved in chemokine-mediated immune cell trafficking and antigen presentation, likely promoting immune cell recruitment. Furthermore, tissue-specific imprinting influences cDC2 plasticity not only within tumors but also in non-malignant tissues, as they were found to have the greatest number of differentially expressed genes (DEGs) among DC subsets when comparing normal tissues, indicating a non-negligible role of tissue imprinting in shaping cDC2 functionality. Our findings illuminate cDC adaptations in both tumoral and steady state conditions, highlighting their functional plasticity and role in immune cell recruitment, driven by tissue imprinting and paving the way for tailored immunotherapies. Understanding cDC2-TME interactions could enhance therapies and position cDC2s as fire starters for cold tumors.