AXL limits the mobilization of cholesterol to regulate dendritic cell maturation and the immunogenic response to cancer

Abstract

SummaryWe previously found that uptake of cellular debris prompts conventional dendritic cells (cDCs) to undergo maturation. This transformation results in DCs entering the molecular state termed ‘mregDC’. In this state, mregDCs dampen their ability to acquire new antigens, upregulate chemokine receptors to migrate to lymphoid organs, and upregulate MHC-I and -II, co-stimulatory, and -inhibitory molecules to promote the differentiation of antigen-specific T cells. Here, we show that cholesterol mobilization – through bothde novosynthesis and the acquisition of the metabolite during debris uptake – drives cDCs to mature into mregDCs. This cholesterol is used to assemble lipid nanodomains on the plasma membrane of mregDCs to support cell surface expression of maturation markers. This process is dependent on bothde novosynthesis and Niemann-Pick disease type C1 (NPC1), which shuttles cholesterol from the endolysosomal pathway. Specifically, NPC1 mediated the accumulation of IFN-ɣ receptor (IFNɣR) in cell surface lipid nanodomains, enabling optimal IFNɣR signaling required for IL-12 production and efficient T cell activation. Importantly, we also show that the receptor tyrosine kinase AXL constitutively dampens the cholesterol-dependent construction of lipid nanodomains on mregDCs; its deletion from cDCs enhance mregDC immunogenicity and yielded potent anti-tumor immunity in an experimental model of lung cancer. Altogether, our findings present novel insights into the mobilization of cholesterol for proper immune receptor signaling as a basis for cDC maturation and the novel role of AXL as a central regulator of this process that can be therapeutically targeted to leverage the immunostimulatory features of mregDCs.

The unfolded protein sensor IRE1a is essential for homeostatic dendritic cell maturation

“…Signals driving homeostatic DC maturation in steady state conditions have long remained enigmatic 21 . Recently, several labs uncovered an essential role for apoptotic cell (AC) engulfment and cholesterol metabolic pathways at the heart of cDC1 maturation 20,22,23 . We previously noted that injection of exogenous apoptotic thymocytes boosted engulfment in splenic cDC1s and triggered their homeostatic maturation with a peak observed at 12h post-intravenous injection 20 (Fig.…”