Type I interferon activates MHC class I-dressed CD11b+ conventional dendritic cells to promote protective anti-tumor CD8+ T cell immunity

Abstract

Tumor-infiltrating dendritic cells (DCs) assume varied functional states that impact anti-tumor immunity. To delineate the DC states associated with productive anti-tumor T cell immunity, we compared spontaneously regressing and progressing tumors. Tumor-reactive CD8⁺ T cell responses in Batf3^-/- mice lacking type 1 DCs (DC1s) were lost in progressor tumors but preserved in regressor tumors. Transcriptional profiling of intra-tumoral DCs within regressor tumors revealed an activation state of CD11b⁺ conventional DCs (DC2s) characterized by expression of interferon (IFN)-stimulated genes (ISGs) (ISG⁺ DCs). ISG⁺ DC-activated CD8⁺ T cells ex vivo comparably to DC1. Unlike cross-presenting DC1, ISG⁺ DCs acquired and presented intact tumor-derived peptide-major histocompatibility complex class I (MHC class I) complexes. Constitutive type I IFN production by regressor tumors drove the ISG⁺ DC state, and activation of MHC class I-dressed ISG⁺ DCs by exogenous IFN-β rescued anti-tumor immunity against progressor tumors in Batf3^-/- mice. The ISG⁺ DC gene signature is detectable in human tumors. Engaging this functional DC state may present an approach for the treatment of human disease.

Keywords: MHC class I dressing; T cell exhaustion; anti-tumor immunity; cross-presentation; dendritic cells; immunotherapy; optimal anti-tumor immunity; tumor regression; type 2 dendritic cells; type I interferon.