Dynamic changes in cellular infiltrates with repeated cutaneous vaccination: a histologic and immunophenotypic analysis.
BACKGROUND
Melanoma vaccines have not been optimized. Adjuvants are added to activate dendritic cells (DCs) and to induce a favourable immunologic milieu, however, little is known about their cellular and molecular effects in human skin. We hypothesized that a vaccine in incomplete Freund's adjuvant (IFA) would increase dermal Th1 and Tc1-lymphocytes and mature DCs, but that repeated vaccination may increase regulatory cells.


METHODS
During and after 6 weekly immunizations with a multipeptide vaccine, immunization sites were biopsied at weeks 0, 1, 3, 7, or 12. In 36 participants, we enumerated DCs and lymphocyte subsets by immunohistochemistry and characterized their location within skin compartments.


RESULTS
Mature DCs aggregated with lymphocytes around superficial vessels, however, immature DCs were randomly distributed. Over time, there was no change in mature DCs. Increases in T and B-cells were noted. Th2 cells outnumbered Th1 lymphocytes after 1 vaccine 6.6:1. Eosinophils and FoxP3+ cells accumulated, especially after 3 vaccinations, the former cell population most abundantly in deeper layers.


CONCLUSIONS
A multipeptide/IFA vaccine may induce a Th2-dominant microenvironment, which is reversed with repeat vaccination. However, repeat vaccination may increase FoxP3+T-cells and eosinophils. These data suggest multiple opportunities to optimize vaccine regimens and potential endpoints for monitoring the effects of new adjuvants.


BACKGROUND
ClinicalTrials.gov Identifier: NCT00705640.
Schaefer
Jochen T
JT
Human Immune Therapy Center, University of Virginia, Charlottesville, VA, USA.
Patterson
James W
JW
Deacon
Donna H
DH
Smolkin
Mark E
ME
Petroni
Gina R
GR
Jackson
Emily M
EM
Slingluff
Craig L
CL
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D019496:Cancer Vaccines / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping / Q000379:methods*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology*; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology*; D008875:Middle Aged; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology*; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D014611:Vaccination
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors