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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
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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
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Journal Article
Activation, dysfunction and retention of T cells in vaccine sites after injection of incomplete Freund’s adjuvant, with or without peptide
2013
Overview
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 (T
CD8
). The vast majority of T
CD8
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. T
CD8
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). T
CD8
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 T
CD8
within VSME may represent a significant mechanism underlying transient immune responses and low clinical response rates to peptide vaccines administered in IFA.
Publisher
Springer-Verlag,Springer Nature B.V
Subject
/ Antigens, Differentiation, T-Lymphocyte - metabolism
/ Cancer Vaccines - administration & dosage
/ Cancer Vaccines - immunology
/ CD8-Positive T-Lymphocytes - immunology
/ Female
/ Freund's Adjuvant - administration & dosage
/ Freund's Adjuvant - immunology
/ Humans
/ Integrin alpha1beta1 - metabolism
/ Interferon-gamma - metabolism
/ Lectins, C-Type - metabolism
/ Leukocytes, Mononuclear - immunology
/ Lipids - administration & dosage
/ Male
/ Medicine
/ Melanoma
/ Oncology
/ Patients
/ Peptides
