β2-Integrin Adhesion Regulates Dendritic Cell Epigenetic and Transcriptional Landscapes to Restrict Dendritic Cell Maturation and Tumor Rejection
| Autor: | Mette Ilander, Vincenzo Cerullo, Maria Sokolova, Susanna C. Fagerholm, Imrul Faisal, Robert Tallberg, Maria K. Vartiainen, Jose-Maria Gonzalez-Granado, Heidi Harjunpää, Carla Guenther, Ronen Alon, Manlio Fusciello |
|---|---|
| Přispěvatelé: | Veterinary Biosciences, Integrins in immunity, Molecular and Integrative Biosciences Research Programme, ImmunoViroTherapy Lab, Division of Pharmaceutical Biosciences, Institute of Biotechnology, HUS Comprehensive Cancer Center, Nuclear organization by actin, Drug Research Program, Faculty Common Matters (Faculty of Biology and Environmental Sciences) |
| Rok vydání: | 2021 |
| Předmět: |
CHROMATIN
Cancer Research medicine.medical_treatment Immunology Integrin Biology Epigenesis Genetic HETEROCHROMATIN Mice 03 medical and health sciences 0302 clinical medicine INFLAMMATION Cancer immunotherapy Neoplasms Histone methylation medicine Animals Humans Epigenetics 030304 developmental biology CD86 0303 health sciences Cell Differentiation Dendritic Cells Dendritic cell DEGRADATION INTEGRINS Chromatin Cell biology 317 Pharmacy CD18 Antigens biology.protein H3K4me3 Signal Transduction 030215 immunology |
| Zdroj: | Cancer Immunology Research |
| ISSN: | 2326-6074 2326-6066 |
| DOI: | 10.1158/2326-6066.cir-21-0094 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|