beta2-integrin adhesion regulates dendritic cell epigenetic and transcriptional landscapes to restrict dendritic cell maturation and tumor rejection

Cancer Immunol Res. 2021 Sep 24:canimm.0094.2021. doi: 10.1158/2326-6066.CIR-21-0094. Online ahead of print.ABSTRACTDendritic cells (DCs), the classical antigen-presenting cells of the immune system, switch from an adhesive, phagocytic phenotype in tissues, to a mature, non-adhesive 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-DCs) 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, IL-12 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-regula...
Source: Cell Research - Category: Cytology Authors: Source Type: research