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

ABSTRACT: Tumor-infiltrating antigen-presenting cells, such as dendritic cells (DC), have the capacity to shape anti-tumor T cell responses. While tremendous progress has been made in unraveling the role of Batf3-driven DC1 in the anti-tumor immune response, the contributions of other tumor-infiltrating DC subsets remain poorly understood. Furthermore, tumor-infiltrating DC exist in a range of functional states with differential impacts on anti-tumor immunity. In this study, we sought to identify and characterize the functionally relevant DC states associated with a productive anti-tumor T cell response. By comparing the DC infiltrate of spontaneously regressing tumors and progressing tumors, we identified a novel activation state of CD11b+ conventional DC in tumors, which expressed an interferon-stimulated gene signature (‘ISG+ DC’). ISG+ DC were activated by type-I-interferon-induced signaling and could generate protective CD8+ T cell responses by cross-dressing with tumor-derived peptide-MHC complexes. Stimulatory ISG+ DC induced by exogenous IFNβ addition drove robust anti-tumor T cell responses in poorly immunogenic tumors even in the absence of DC1.

ORGANISM(S): Mus musculus

PROVIDER: GSE151990 | GEO | 2022/01/13

REPOSITORIES: GEO

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

Project description:Tumor-infiltrating antigen-presenting cells, such as dendritic cells (DC), have the capacity to shape anti-tumor T cell responses. While tremendous progress has been made in unraveling the role of Batf3-driven DC1 in the anti-tumor immune response, the contributions of other tumor-infiltrating DC subsets remain poorly understood. Furthermore, tumor-infiltrating DC exist in a range of functional states with differential impacts on anti-tumor immunity. In this study, we sought to identify and characterize the functionally relevant DC states associated with a productive anti-tumor T cell response. By comparing the DC infiltrate of spontaneously regressing tumors and progressing tumors, we identified a novel activation state of CD11b+ conventional DC in tumors, which expressed an interferon-stimulated gene signature (‘ISG+ DC’). ISG+ DC were activated by type-I-interferon-induced signaling and could generate protective CD8+ T cell responses by cross-dressing with tumor-derived peptide-MHC complexes. Stimulatory ISG+ DC induced by exogenous IFNβ addition drove robust anti-tumor T cell responses in poorly immunogenic tumors even in the absence of DC1.

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Transcription factor Etv6 controls functional differentiation of cross-presenting classical dendritic cells [RNA-Seq]

Project description:An IRF8-dependent subset of classical dendritic cells (cDCs), termed DC1, effectively cross-primes CD8+ T cells and facilitates antitumor T cell responses. Etv6 is an ETS family transcription factor that controls hematopoietic stem and progenitor cell (HSPC) function. We report that like HSPC, cDCs express Etv6 but not its antagonist ETS1, whereas interferon-producing plasmacytoid dendritic cells (pDCs) express both factors. Deletion of Etv6 in the bone marrow reduced the generation of DC1-like cells in vitro and the differentiation of DC1 in vivo, including the loss of signature marker CD8a. Global expression and chromatin profiling of Etv6-deficient DCs revealed impaired lineage identity of DC1, including the reduction of cDC signature and upregulation of pDC signature. Accordingly, DC-specific Etv6 deletion impaired CD8+ T cell cross-priming and tumor-specific CD8+ T cell responses. These results identify Etv6 as a regulator of DC1 differentiation and functional fitness that indirectly facilitates T cell cross-priming and antitumor immunity.

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Transcription factor Etv6 controls functional differentiation of cross-presenting classical dendritic cells [ATAC-Seq]

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2023-05-11 | PXD035002 | Pride

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