Interferon-induced lysosomal membrane permeabilization and death cause cDC1-deserts in tumors

Abstract

The landscape of migratory conventional dendritic cells (cDCs) comprises XCR1+CD11b- cDC1s, XCR1-CD11b+ cDC2s and intermediate XCR1low/negCD11b- states. cDC1 are unique in their ability to cross-prime lymph node CD8 T cells in a CD4 T cell-dependent manner. In perturbed cancer states cDC1s become particularly scarce in tumors and tumor draining lymph nodes, which decreases T cell infiltration, immunotherapy responses and patient survival. The causes of cDC1 paucity are not fully understood and no specific therapy currently exists. Here, we find that cDC1s undergo apoptosis in tumor microenvironments. Gene expression analysis of independent murine and human RNA sequencing datasets point to a shared cDC1 lysosomal stress response state across various tumors. Modeling primary cDC1 behavior in lung tumors in vivo and ex vivo, we show that two distinct yet interconnected pathways converge to cause apoptosis of cDC1: mTOR inhibition leads to an increase in the proteolytic activity of lysosomes, while lysosomal membrane permeabilization (LMP) allows the release of proteolytic enzymes to the cytosol and apoptotic death. Pathway and regulon analysis of the cDC1 transcriptome suggest that mTOR inhibition and lysosomal stress happen downstream of type I IFNs. Accordingly, exposure of the Mutu cDC1 line to type I IFNs inhibits mTOR, stresses lysosomes and triggers LMP and death. Further supporting this finding, in mixed bone-marrow chimeras IFNRA deletion rescues primary cDC1s from mTOR inhibition, lysosomal stress, LMP and death. We have therefore elucidated IFN-induced lysosomal death as a key mechanism of cDC1s paucity in tumors that should be prevented to increase tumor immunity through reinvigoration of the cDC1 pool.