Cancer Immunology, Immunotherapy

, Volume 62, Issue 7, pp 1149–1159

Activation, dysfunction and retention of T cells in vaccine sites after injection of incomplete Freund’s adjuvant, with or without peptide

  • Elise P. Salerno
  • Sofia M. Shea
  • Walter C. Olson
  • Gina R. Petroni
  • Mark E. Smolkin
  • Chantel McSkimming
  • Kimberly A. Chianese-Bullock
  • Craig L. SlingluffJr.
Original Article

DOI: 10.1007/s00262-013-1435-5

Cite this article as:
Salerno, E.P., Shea, S.M., Olson, W.C. et al. Cancer Immunol Immunother (2013) 62: 1149. doi:10.1007/s00262-013-1435-5

Abstract

We conducted a randomized clinical trial in 45 patients with resected AJCC stage IIB-IV melanoma to characterize cellular and molecular events at sites of immunization with incomplete Freund’s adjuvant (IFA) alone, or a melanoma vaccine in IFA. At a primary vaccine site, all patients received a multi-peptide melanoma vaccine in IFA. At a replicate vaccine site, which was biopsied, group 1 received IFA only; group 2 received vaccine in IFA. Lymphocytes isolated from replicate vaccine site microenvironments (VSME) were compared to time-matched peripheral blood mononuclear cells (PBMC) in ELISpot and flow cytometry assays. Compared to PBMC, the VSME had fewer naïve and greater proportions of effector memory CD8+ T cells (TCD8). The vast majority of TCD8 within the VSME were activated (CD69+), with a concentration of antigen-specific (tetramerpos) cells in the VSME, particularly in vaccine sites with peptide (group 2). CXCR3+ lymphocytes were concentrated in the VSME of all patients, suggesting IFA-induced chemokine recruitment. TCD8 expression of retention integrins αEβ7 and α1β1 was elevated in VSME, with the highest levels observed in antigen-specific cells in VSME containing peptide (group 2). TCD8 retained in the VSME of both groups were strikingly dysfunctional, with minimal IFN-γ production in response to peptide stimulation and few tetramerpos cells producing IFN-γ. These data suggest that vaccine-induced selective retention and dysfunction of antigen-specific TCD8 within VSME may represent a significant mechanism underlying transient immune responses and low clinical response rates to peptide vaccines administered in IFA.

Keywords

Human  T cell  Incomplete Freund’s adjuvant  Peptide vaccine  Melanoma  CIMT 2012 Integrins Melanoma vaccine 

Abbreviations

CLA

Cutaneous leukocyte antigen

HEV

High endothelial venule

IFA

Incomplete Freund’s adjuvant

PBMC

Peripheral blood mononuclear cell

TCM

Central memory T cell (CD45RAneg/CCR7+)

TEM

Effector memory T cell (CD45RAneg/CCR7neg)

TEMRA

CD45RApos effector memory T cell (CD45RAneg/CCR7neg)

TLO

Tertiary lymphoid organ

Tnaive

Naïve T cell (CD45RA+/CCR7+)

VSME

Vaccine site microenvironment

Supplementary material

262_2013_1435_MOESM1_ESM.pdf (391 kb)
Supplementary material 1 (PDF 390 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Elise P. Salerno
    • 1
  • Sofia M. Shea
    • 2
  • Walter C. Olson
    • 1
  • Gina R. Petroni
    • 3
  • Mark E. Smolkin
    • 3
  • Chantel McSkimming
    • 4
  • Kimberly A. Chianese-Bullock
    • 1
  • Craig L. SlingluffJr.
    • 1
    • 5
  1. 1.Division of Surgical Oncology, Department of SurgeryUniversity of VirginiaCharlottesvilleUSA
  2. 2.Department of PathologyUniversity of VirginiaCharlottesvilleUSA
  3. 3.Department of Public Health SciencesUniversity of VirginiaCharlottesvilleUSA
  4. 4.Cardiovascular Research CenterUniversity of VirginiaCharlottesvilleUSA
  5. 5.UVA Health SystemCharlottesvilleUSA

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