title: The vascular disrupting agent, DMXAA, directly activates dendritic cells through a MyD88-independent mechanism and generates antitumor cytotoxic T lymphocytes.
abstract: 5,6-Di-methylxanthenone-4-acetic acid (DMXAA) is a small molecule in the flavanoid class that has antitumor activity. Although classified as a "vascular disrupting agent," we have recently conducted studies showing that DMXAA has remarkable efficacy in a range of tumors, working primarily as an immune modulator that activates tumor-associated macrophages and induces a subsequent CD8(+) T-cell-mediated response. To more completely analyze the effect of DMXAA on CD8(+) T-cell generation, we treated mice bearing tumors derived from EG7 thymoma cells that express the well-characterized chicken ovalbumin neotumor antigen. Treatment with DMXAA led to cytokine release, tumor cell necrosis, and ultimately reduction in tumor size that was lymphocyte dependent. Within 24 h of administration, we observed dendritic cell activation in tumor-draining lymph nodes (TDLN). This was followed by a rapid and marked increase in the number of tetramer-specific CD8(+) T cells in the spleens of treated animals. In contrast, the vascular disrupting agent combretastatin A4-phosphate, which caused a similar amount of immediate tumor necrosis, did not activate dendritic cells, nor induce an effective antitumor response. Using in vitro systems, we made the observation that DMXAA has the ability to directly activate mouse dendritic cells, as measured by increased expression of costimulatory molecules and proinflammatory cytokine release via a pathway that does not require the Toll-like receptor adaptor molecule MyD88. DMXAA thus has the ability to activate tumor-specific CD8(+) T cells through multiple pathways that include induction of tumor cell death, release of stimulatory cytokines, and direct activation of dendritic cells.
authors.affiliation: Thoracic Oncology Research Laboratory, Department of Medicine, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Africa
authors.initials: A
authors.lastname: Wallace
authors.forename: David F
authors.initials: DF
authors.lastname: LaRosa
authors.forename: Veena
authors.initials: V
authors.lastname: Kapoor
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Guanjun
authors.initials: G
authors.lastname: Cheng
authors.forename: Arminder
authors.initials: A
authors.lastname: Jassar
authors.forename: Aaron
authors.initials: A
authors.lastname: Blouin
authors.forename: Lai-Ming
authors.initials: LM
authors.lastname: Ching
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D002645:Chickens; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D009336:Necrosis; D009368:Neoplasm Transplantation; D010047:Ovalbumin / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D053594:Myeloid Differentiation Factor 88; D044004:Xanthones; C066668:vadimezan; D010047:Ovalbumin