title: PD-1 or PD-L1 Blockade Restores Antitumor Efficacy Following SSX2 Epitope-Modified DNA Vaccine Immunization.
abstract: DNA vaccines have demonstrated antitumor efficacy in multiple preclinical models, but low immunogenicity has been observed in several human clinical trials. This has led to many approaches seeking to improve the immunogenicity of DNA vaccines. We previously reported that a DNA vaccine encoding the cancer-testis antigen SSX2, modified to encode altered epitopes with increased MHC class I affinity, elicited a greater frequency of cytolytic, multifunctional CD8(+) T cells in non-tumor-bearing mice. We sought to test whether this optimized vaccine resulted in increased antitumor activity in mice bearing an HLA-A2-expressing tumor engineered to express SSX2. We found that immunization of tumor-bearing mice with the optimized vaccine elicited a surprisingly inferior antitumor effect relative to the native vaccine. Both native and optimized vaccines led to increased expression of PD-L1 on tumor cells, but antigen-specific CD8(+) T cells from mice immunized with the optimized construct expressed higher PD-1. Splenocytes from immunized animals induced PD-L1 expression on tumor cells in vitro. Antitumor activity of the optimized vaccine could be increased when combined with antibodies blocking PD-1 or PD-L1, or by targeting a tumor line not expressing PD-L1. These findings suggest that vaccines aimed at eliciting effector CD8(+) T cells, and DNA vaccines in particular, might best be combined with PD-1 pathway inhibitors in clinical trials. This strategy may be particularly advantageous for vaccines targeting prostate cancer, a disease for which antitumor vaccines have demonstrated clinical benefit and yet PD-1 pathway inhibitors alone have shown little efficacy to date.
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Rekoske
authors.affiliation: Department of Oncology, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Heath A
authors.initials: HA
authors.lastname: Smith
authors.affiliation: The Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Olson
authors.affiliation: The Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Brett B
authors.initials: BB
authors.lastname: Maricque
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin. The Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin. dm3@medicine.wisc.edu.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: McNeel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D015870:Gene Expression; D006801:Humans; D007114:Immunization; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; D019496:Cancer Vaccines; D000939:Epitopes; D010446:Peptide Fragments; D061026:Programmed Cell Death 1 Receptor; D019444:Vaccines, DNA