title: Targeted therapeutic remodeling of the tumor microenvironment improves an HER-2 DNA vaccine and prevents recurrence in a murine breast cancer model.
abstract: The tumor microenvironment (TME) mediates immunosuppression resulting in tumor cell escape from immune surveillance and cancer vaccine failure. Immunosuppression is mediated by the STAT-3 transcription factor, which potentiates signaling in tumor and immune cells. Because immunosuppression continues to be a major inhibitor of cancer vaccine efficacy, we examined in this study whether therapeutically targeted delivery of a synthetic STAT-3 inhibitor to the TME, combined with an HER-2 DNA vaccine can improve immune surveillance against HER-2(+) breast cancer and prevent its recurrence. To this end, we developed a novel ligand-targeted nanoparticle (NP) encapsulating a CDDO-Im payload capable of specific delivery to the TME, which showed an effective therapeutic inhibition of STAT-3 activation in primary tumors. Furthermore, we showed that treatment with these NPs resulted in priming of the immune TME, characterized by increased IFN-γ, p-STAT-1, GM-CSF, IL-2, IL-15, and IL-12b and reduced TGF-β, IL-6, and IL-10 protein expression. In addition, we found significantly increased tumor infiltration by activated CD8(+) T cells, M1 macrophages, and dendritic cells. These changes correlated with delayed growth of orthotopic 4TO7 breast tumors and, when combined with an HER-2 DNA vaccine, prevented HER-2(+) primary tumor recurrence in immunocompetent mice. Furthermore, antitumor T-cell responses were enhanced in splenocytes isolated from mice treated with this combination therapy. Together, these data show effective protection from cancer recurrence through improved immune surveillance against a tumor-specific antigen.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, University of California, San Diego, La Jolla, California, USA.
authors.forename: Debbie
authors.initials: D
authors.lastname: Liao
authors.forename: Ze
authors.initials: Z
authors.lastname: Liu
authors.forename: Wolfgang J
authors.initials: WJ
authors.lastname: Wrasidlo
authors.forename: Yunping
authors.initials: Y
authors.lastname: Luo
authors.forename: Giang
authors.initials: G
authors.lastname: Nguyen
authors.forename: Tingmei
authors.initials: T
authors.lastname: Chen
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Reisfeld
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000628:therapy*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D007165:Immunosuppression Therapy; D008325:Mammary Neoplasms, Experimental / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D059016:Tumor Microenvironment; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*
chemical_list: D019496:Cancer Vaccines; D018719:Erb-b2 Receptor Tyrosine Kinases; D050796:STAT3 Transcription Factor; D019444:Vaccines, DNA