Toll-like receptor 9 dependent dendritic cells-NK cooperation in anti-tumor immune control 2381

Abstract Description The release of sterile Danger-Associated Molecular Pattern signals (DAMPs) by a tumor promotes activation of tissue dendritic cells (DCs) via Toll-Like Receptors (TLRs) and their migration to tumor draining lymph nodes (LNs) to present tumor antigens to T lymphocytes and to recruit NK cells. While DAMPs are important for efficient anti-tumor immune response, different danger signals may have inhibitory effect on each other. We show that Toll like receptor 9 (TLR9) signaling in tumor associated dendritic cells (DCs) is tolerogenic in contrast to what is observed in systemic TLR9 deficient mice. Indeed, mice with DC-restricted loss of TLR9 display slower melanoma growth and extended survival. TLR9-deficient DCs migrate less to the draining lymph nodes and accumulate in the tumor where they mature and recruit NK cells. Anti-tumor effect is dependent on NK cells, as their depletion severely accelerated tumor growth in mice lacking the expression of TLR9 in DCs but not in control mice. We also show that with tumor progression a small, but non-negligible proportion of tumor associated T and NK cells acquire TLR9 expression. Altogether our results suggest that TLR9 signal is required for DC migration, but not for DC maturation, while TLR9 signal in lymphocytes might promote anti-tumor immune response. Funding Sources Supported by INCA PLBIO19-075, Ligue contre le Cancer Regional Subvention 1FI15548XZBD and INCA PLBIO2023-171 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)