TTT/AAA β2-integrin knock-in (β2-integrin KI) mice have inactive β2-integrin adhesion receptors. Comparisons between β2-integrin KI DCs and WT DCs indicated that active β2-integrins restricted DC maturation and migration. β2-integrin KI DCs induced increased tumor suppression in vivo and increased tumor-specific CD8+ T cell responses in TILs, spleens, and DLNs. β2-integrins regulated the DC epigenetic state (histone methylation) and transcriptional landscape through transcription factors, particularly Ikaros/RelA. Immune pathways mediated by mechanical cues through β2-integrin represent potential new targets for DC-based immunotherapies.

Contributed by Margot O’Toole

ABSTRACT: Dendritic 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-regulated epigenetic landscape in wild type (WT) 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.

Author Info: (1) Molecular and Integrative Biosciences Research Programme, University of Helsinki. (2) Molecular and Integrative Biosciences Research Programme, University of Helsinki. (3) DPDR

Author Info: (1) Molecular and Integrative Biosciences Research Programme, University of Helsinki. (2) Molecular and Integrative Biosciences Research Programme, University of Helsinki. (3) DPDR, University of Helsinki. (4) Institute of Biotechnology, University of Helsinki. (5) Molecular and Integrative Biosciences Research Programme, University of Helsinki. (6) Faculty of biological and environmental sciences, University of Helsinki. (7) Molecular and Integrative Biosciences Research Programme, University of Helsinki. (8) Institute of Biotechnology, University of Helsinki. (9) Department of Immunology, Weizmann Institute of Science. (10) Universidad Autonoma de Madrid, Instituto de Investigacion Hospital 12 de Octubre (imas12). (11) Laboratory of ImmunoViroTherapy, Drug Rfesearch Program, University of Helsinki. (12) Molecular and Integrative Biosciences Research Programme, University of Helsinki susanna.fagerholm@helsinki.fi.