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

Ellen Duong; Tim B Fessenden; Emi Lutz; Teresa Dinter; Leon Yim; Sarah Blatt; Arjun Bhutkar; Karl Dane Wittrup; Stefani Spranger

doi:10.1016/j.immuni.2021.10.020

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

Immunity. 2022 Feb 8;55(2):308-323.e9. doi: 10.1016/j.immuni.2021.10.020. Epub 2021 Nov 19.

Authors

Ellen Duong¹, Tim B Fessenden², Emi Lutz³, Teresa Dinter¹, Leon Yim², Sarah Blatt², Arjun Bhutkar², Karl Dane Wittrup³, Stefani Spranger⁴

Affiliations

¹ Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA; Department of Biology, MIT, Cambridge, MA, USA.
² Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA.
³ Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA; Department of Biological Engineering, MIT, Cambridge, MA, USA.
⁴ Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA; Department of Biology, MIT, Cambridge, MA, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA. Electronic address: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Neoplasm / immunology
CD11b Antigen / immunology
CD8-Positive T-Lymphocytes / immunology*
Cross-Priming
Dendritic Cells / drug effects
Dendritic Cells / immunology*
Histocompatibility Antigens Class I / immunology*
Interferon Type I / immunology*
Interferon-beta / administration & dosage
Interferon-beta / pharmacology
Lymphocytes, Tumor-Infiltrating / immunology*
Mice
Neoplasms / immunology
Receptors, Interferon / immunology
Signal Transduction / immunology
Tumor Microenvironment / immunology

Substances

Antigens, Neoplasm
CD11b Antigen
Histocompatibility Antigens Class I
Interferon Type I
Itgam protein, mouse
Receptors, Interferon
Interferon-beta

Abstract

Publication types

MeSH terms

Substances

Grants and funding