β2-Integrin Adhesion Regulates Dendritic Cell Epigenetic and Transcriptional Landscapes to Restrict Dendritic Cell Maturation and Tumor Rejection.
Carla GuentherImrul FaisalManlio FuscielloMaria SokolovaHeidi HarjunpääMette IlanderRobert TallbergMaria Kristina VartiainenRonen AlonJose-Maria Gonzalez-GranadoVincenzo CerulloSusanna Carola FagerholmPublished in: Cancer immunology research (2021)
Dendritic cells (DC), the classic antigen-presenting cells of the immune system, switch from an adhesive, phagocytic phenotype in tissues, to a mature, nonadhesive phenotype that enables migration to lymph nodes to activate T cells and initiate antitumor responses. Monocyte-derived DCs are used in cancer immunotherapy, but their clinical efficacy is limited. Here, we show that cultured bone marrow-derived DCs (BM-DC) expressing dysfunctional β2-integrin adhesion receptors displayed enhanced tumor rejection capabilities in B16.OVA and B16-F10 melanoma models. This was associated with an increased CD8+ T-cell response. BM-DCs expressing dysfunctional β2-integrins or manipulated to disrupt integrin adhesion or integrin/actin/nuclear linkages displayed spontaneous maturation in ex vivo cultures (increased costimulatory marker expression, IL12 production, and 3D migration capabilities). This spontaneous maturation was associated with an altered DC epigenetic/transcriptional profile, including a global increase in chromatin accessibility and H3K4me3/H3K27me3 histone methylation. Genome-wide analyses showed that H3K4me3 methylation was increased on DC maturation genes, such as CD86, Il12, Ccr7, and Fscn1, and revealed a role for a transcription factor network involving Ikaros and RelA in the integrin-regulated phenotype of DCs. Manipulation of the integrin-regulated epigenetic landscape in wild-type ex vivo-cultured BM-DCs enhanced their functionality in tumor rejection in vivo. Thus, β2-integrin-mediated adhesion to the extracellular environment plays an important role in restricting DC maturation and antitumor responses through regulation of the cellular epigenetic and transcriptional landscape. Targeting β2-integrins could therefore be a new strategy to improve the performance of current DC-based cancer immunotherapies.
Keyphrases
- dendritic cells
- dna methylation
- transcription factor
- genome wide
- cell migration
- gene expression
- cell adhesion
- regulatory t cells
- immune response
- wild type
- lymph node
- biofilm formation
- endothelial cells
- mesenchymal stem cells
- poor prognosis
- induced apoptosis
- copy number
- cell proliferation
- case report
- squamous cell carcinoma
- cell death
- dna binding
- heat stress
- peripheral blood
- long non coding rna
- heat shock protein
- pi k akt
- network analysis
- locally advanced