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Activation, dysfunction and retention of T cells in vaccine sites after injection of incomplete Freund's adjuvant, with or without peptide.
- Source :
-
Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2013 Jul; Vol. 62 (7), pp. 1149-59. Date of Electronic Publication: 2013 May 09. - Publication Year :
- 2013
-
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 (tetramer(pos)) 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 tetramer(pos) 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.
- Subjects :
- Antigens, CD metabolism
Antigens, Differentiation, T-Lymphocyte metabolism
Cancer Vaccines administration & dosage
Female
Freund's Adjuvant administration & dosage
Humans
Integrin alpha1beta1 metabolism
Integrins metabolism
Interferon-gamma metabolism
Lectins, C-Type metabolism
Lipids administration & dosage
Lymphocyte Activation
Male
Melanoma metabolism
Middle Aged
Receptors, CXCR3 metabolism
CD8-Positive T-Lymphocytes immunology
Cancer Vaccines immunology
Freund's Adjuvant immunology
Leukocytes, Mononuclear immunology
Lipids immunology
Melanoma immunology
Peptides immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0851
- Volume :
- 62
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cancer immunology, immunotherapy : CII
- Publication Type :
- Academic Journal
- Accession number :
- 23657629
- Full Text :
- https://doi.org/10.1007/s00262-013-1435-5