title: Protection against HPV-16-Associated Tumors Requires the Activation of CD8+ Effector Memory T Cells and the Control of Myeloid-Derived Suppressor Cells.
abstract: Active anticancer immunotherapeutic approaches have been shown to induce cellular or humoral immune responses in patients, but, thus far, the observed outcomes did not ensure their recommendation for clinical use. The induction of tumor-specific CD8(+) T cells, although required for the clearance of most solid tumors, was shown to be insufficient for the development of a successful immunotherapeutic approach. The suppressive immune environment triggered by tumors, including the expansion of myeloid-derived suppressor cells (MDSC), is detrimental to the development of antitumor immune responses and precludes the generation of more promising clinical outcomes. In this work, we characterized the CD8(+) T-cell population specifically involved in the control of tumor growth and the role of MDSCs after administration of an antitumor therapeutic DNA vaccine targeting human papillomavirus type 16 (HPV-16)-associated tumors. Activation of cytotoxic high-avidity CD8(+) T cells with an effector memory phenotype was found in mice grafted with tumor cells expressing the HPV-16 oncoproteins. In addition, MDSC antibody depletion further enhanced the immunotherapeutic effects of the vaccine, resulting in the complete eradication of tumor cells. Collectively, the current results indicate that the simultaneous control of MDSCs and activation of high-avidity tumor-specific effector memory CD8(+) T cells are key features for tumor protection by immunotherapeutic approaches and deserve further testing under clinical conditions. Mol Cancer Ther; 15(8); 1920-30. ©2016 AACR.
authors.affiliation: Department of Microbiology, Vaccine Development Laboratory, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. modiniz@usp.br.
authors.forename: Mariana O
authors.initials: MO
authors.lastname: Diniz
authors.affiliation: Department of Microbiology, Vaccine Development Laboratory, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Natiely S
authors.initials: NS
authors.lastname: Sales
authors.affiliation: Department of Microbiology, Vaccine Development Laboratory, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Jamile R
authors.initials: JR
authors.lastname: Silva
authors.affiliation: Department of Microbiology, Vaccine Development Laboratory, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Luís Carlos S
authors.initials: LC
authors.lastname: Ferreira
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology*; D006801:Humans; D007114:Immunization; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology* / Q000378:metabolism; D009369:Neoplasms / Q000209:etiology / Q000401:mortality / Q000473:pathology / Q000628:therapy; D030361:Papillomavirus Infections / Q000150:complications / Q000276:immunology* / Q000821:virology; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D047368:Tumor Burden / Q000276:immunology; D019444:Vaccines, DNA / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D019496:Cancer Vaccines; D019444:Vaccines, DNA; D007371:Interferon-gamma