title: Therapeutic antitumor potential of endoglin-based DNA vaccine combined with immunomodulatory agents.
abstract: Therapy targeting tumor blood vessels ought to inhibit tumor growth. However, tumors become refractory to antiangiogenic drugs. Therefore, therapeutic solutions should be sought to address cellular resistance to antiangiogenic therapy. In this regard, reversal of the proangiogenic and immunosuppressive phenotype of cancer cells, and the shift of the tumor microenvironment towards more antiangiogenic and immune-stimulating phenotype may hold some promise. In our study, we sought to validate the effects of a combination therapy aimed at reducing tumor blood vessels, coupled with the abrogation of the immunosuppressive state. To achieve this, we developed an oral DNA vaccine against endoglin. This antigen was carried by an attenuated Salmonella Typhimurium and applied before or after tumor cell inoculation into immunocompetent mice. Our results show that this DNA vaccine effectively inhibited tumor growth, in both the prophylactic and therapeutic settings. It also activated both specific and nonspecific immune responses in immunized mice. Activated cytotoxic T-lymphocytes were directed specifically against endothelial and tumor cells overexpressing endoglin. The DNA vaccine inhibited angiogenesis but did not affect wound healing. In combination with interleukin-12-mediated gene therapy, or with cyclophosphamide administration, the DNA vaccine resulted in reduced microvessel density and lowered the level of Treg lymphocytes in the experimental tumors. This effectively inhibited tumor growth and prolonged survival of the treated animals. Polarization of tumor milieu, from proangiogenic and immunosuppressive, towards an immunostimulatory and antiangiogenic profile represents a promising avenue in anticancer therapy.
authors.affiliation: Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Jarosz
authors.forename: J
authors.initials: J
authors.lastname: Jazowiecka-Rakus
authors.forename: T
authors.initials: T
authors.lastname: Cichoń
authors.forename: M
authors.initials: M
authors.lastname: Głowala-Kosińska
authors.forename: R
authors.initials: R
authors.lastname: Smolarczyk
authors.forename: A
authors.initials: A
authors.lastname: Smagur
authors.forename: S
authors.initials: S
authors.lastname: Malina
authors.forename: A
authors.initials: A
authors.lastname: Sochanik
authors.forename: S
authors.initials: S
authors.lastname: Szala
mesh_terms: D000818:Animals; D019556:COS Cells; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000494:pharmacology*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D000071063:Endoglin; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000517:prevention & control / Q000628:therapy; D012486:Salmonella typhimurium / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D047368:Tumor Burden / Q000276:immunology; D019444:Vaccines, DNA / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D016207:Cytokines; D000071063:Endoglin; C502004:Eng protein, mouse; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D019444:Vaccines, DNA; D018664:Interleukin-12; D003520:Cyclophosphamide