Intramuscular therapeutic vaccination targeting HPV16 induces T cell responses that localize in mucosal lesions.
About 25% of high-grade cervical intraepithelial neoplasias (CIN2/3) caused by human papillomavirus serotype 16 (HPV16) undergo complete spontaneous regression. However, to date, therapeutic vaccination strategies for HPV disease have yielded limited success when measured by their ability to induce robust peripheral blood T cell responses to vaccine antigen. We report marked immunologic changes in the target lesion microenvironment after intramuscular therapeutic vaccination targeting HPV16 E6/E7 antigens, in subjects with CIN2/3 who had modest detectable responses in circulating T lymphocytes. Histologic and molecular changes, including markedly (average threefold) increased intensity of CD8(+) T cell infiltrates in both the stromal and epithelial compartments, suggest an effector response to vaccination. Postvaccination cervical tissue immune infiltrates included organized tertiary lymphoid-like structures in the stroma subjacent to residual intraepithelial lesions and, unlike infiltrates in unvaccinated lesions, showed evidence of proliferation induced by recognition of cognate antigen. At a molecular level, these histologic changes in the stroma were characterized by increased expression of genes associated with immune activation (CXCR3) and effector function (Tbet and IFNβ), and were also associated with an immunologic signature in the overlying dysplastic epithelium. High-throughput T cell receptor sequencing of unmanipulated specimens identified clonal expansions in the tissue that were not readily detectable in peripheral blood. Together, these findings indicate that peripheral therapeutic vaccination to HPV antigens can induce a robust tissue-localized effector immune response, and that analyses of immune responses at sites of antigen are likely to be much more informative than analyses of cells that remain in the circulation.
Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
Leonel
L
Maldonado
Harvard Skin Disease Research Center and the Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Jessica E
JE
Teague
Inovio Pharmaceuticals Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422, USA.
Matthew P
MP
Morrow
Department of Pathology and Cell Biology and Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10025, USA.
Iveta
I
Jotova
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
T C
TC
Wu
Oncology Biostatistics, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
Chenguang
C
Wang
Adaptive Biotechnologies, 1551 Eastlake Avenue, Seattle, WA 98102, USA.
Cindy
C
Desmarais
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Jean D
JD
Boyer
Department of Pathology and Cell Biology and Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10025, USA.
Benjamin
B
Tycko
Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Harlan S
HS
Robins
Harvard Skin Disease Research Center and the Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Rachael A
RA
Clark
Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.|Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.|Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
Cornelia L
CL
Trimble
D000595:Amino Acid Sequence; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D002451:Cell Compartmentation; D002584:Cervix Uteri / Q000276:immunology / Q000473:pathology / Q000821:virology; D015331:Cohort Studies; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology*; D006801:Humans; D018928:Immunity, Mucosal; D007117:Immunization, Secondary; D007156:Immunologic Memory; D007273:Injections, Intramuscular; D008213:Lymphocyte Activation / Q000276:immunology; D008221:Lymphoid Tissue / Q000473:pathology; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000378:metabolism; D012097:Repressor Proteins; D017154:Stromal Cells / Q000473:pathology; D014611:Vaccination; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology*; D002578:Uterine Cervical Dysplasia / Q000097:blood / Q000276:immunology* / Q000628:therapy* / Q000821:virology
D000956:Antigens, Viral; D019496:Cancer Vaccines; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011948:Receptors, Antigen, T-Cell; D012097:Repressor Proteins; D014765:Viral Vaccines; C059731:oncogene protein E7, Human papillomavirus type 16