title: Accumulation of memory precursor CD8 T cells in regressing tumors following combination therapy with vaccine and anti-PD-1 antibody.
abstract: Immunosuppression in the tumor microenvironment blunts vaccine-induced immune effectors. PD-1/B7-H1 is an important inhibitory axis in the tumor microenvironment. Our goal in this study was to determine the effect of blocking this inhibitory axis during and following vaccination against breast cancer. We observed that using anti-PD-1 antibody and a multipeptide vaccine (consisting of immunogenic peptides derived from breast cancer antigens, neu, legumain, and β-catenin) as a combination therapy regimen for the treatment of breast cancer-bearing mice prolonged the vaccine-induced progression-free survival period. This prolonged survival was associated with increase in number of Tc1 and Tc2 CD8 T cells with memory precursor phenotype, CD27+IL-7RhiT-betlo, and decrease in number of PD-1+ dendritic cells (DC) in regressing tumors and enhanced antigen reactivity of tumor-infiltrating CD8 T cells. It was also observed that blockade of PD-1 on tumor DCs enhanced IL-7R expression on CD8 T cells. Taken together, our results suggest that PD-1 blockade enhances breast cancer vaccine efficacy by altering both CD8 T cell and DC components of the tumor microenvironment. Given the recent success of anti-PD-1 monotherapy, our results are encouraging for developing combination therapies for the treatment of patients with cancer in which anti-PD-1 monotherapy alone may be ineffective (i.e., PD-L1-negative tumors).
authors.affiliation: Authors' Affiliations: Cancer Vaccines and Immune Therapies Program, Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida; and Departments of Immunology and Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Lavakumar
authors.initials: L
authors.lastname: Karyampudi
authors.affiliation: Authors' Affiliations: Cancer Vaccines and Immune Therapies Program, Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida; and Departments of Immunology and Oncology, Mayo Clinic, Rochester, MinnesotaAuthors' Affiliations: Cancer Vaccines and Immune Therapies Program, Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida; and Departments of Immunology and Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Purushottam
authors.initials: P
authors.lastname: Lamichhane
authors.affiliation: Authors' Affiliations: Cancer Vaccines and Immune Therapies Program, Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida; and Departments of Immunology and Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Scheid
authors.affiliation: Authors' Affiliations: Cancer Vaccines and Immune Therapies Program, Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida; and Departments of Immunology and Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Kalli
authors.affiliation: Authors' Affiliations: Cancer Vaccines and Immune Therapies Program, Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida; and Departments of Immunology and Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Barath
authors.initials: B
authors.lastname: Shreeder
authors.affiliation: Authors' Affiliations: Cancer Vaccines and Immune Therapies Program, Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida; and Departments of Immunology and Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: James W
authors.initials: JW
authors.lastname: Krempski
authors.affiliation: Authors' Affiliations: Cancer Vaccines and Immune Therapies Program, Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida; and Departments of Immunology and Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Marshall D
authors.initials: MD
authors.lastname: Behrens
authors.affiliation: Authors' Affiliations: Cancer Vaccines and Immune Therapies Program, Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida; and Departments of Immunology and Oncology, Mayo Clinic, Rochester, MinnesotaAuthors' Affiliations: Cancer Vaccines and Immune Therapies Program, Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida; and Departments of Immunology and Oncology, Mayo Clinic, Rochester, Minnesota kknutson@vgtifl.org.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Knutson
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology* / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000276:immunology; D060890:B7-H1 Antigen / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D018572:Disease-Free Survival; D005260:Female; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology*; D034801:Mastocytoma / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D020395:Receptors, Interleukin-7 / Q000276:immunology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
chemical_list: D000906:Antibodies; D000951:Antigens, Neoplasm; D060890:B7-H1 Antigen; D019496:Cancer Vaccines; C498919:Cd274 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D020395:Receptors, Interleukin-7
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