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

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2013-07, Vol.62 (7), p.1149-1159
• Main Authors: Salerno, Elise P., Shea, Sofia M., Olson, Walter C., Petroni, Gina R., Smolkin, Mark E., McSkimming, Chantel, Chianese-Bullock, Kimberly A., Slingluff, Craig L.
• Format: Article
• Language: English
• Subjects: Antigens; Antigens, CD - metabolism; Antigens, Differentiation, T-Lymphocyte - metabolism; Cancer Research; Cancer therapies; Cancer vaccines; Cancer Vaccines - administration & dosage; Cancer Vaccines - immunology; CD8-Positive T-Lymphocytes - immunology; Clinical trials; Dendritic cells; FDA approval; Female; Freund's Adjuvant - administration & dosage; Freund's Adjuvant - immunology; Humans; Immunology; Integrin alpha1beta1 - metabolism; Integrins - metabolism; Interferon-gamma - metabolism; Lectins, C-Type - metabolism; Leukocytes, Mononuclear - immunology; Lipids - administration & dosage; Lipids - immunology; Lymphocyte Activation; Lymphocytes; Male; Medicine; Medicine & Public Health; Melanoma; Melanoma - immunology; Melanoma - metabolism; Middle Aged; Oncology; Original Article; Patients; Peptides; Peptides - immunology; Receptors, CXCR3 - metabolism; Response rates; Retention
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-013-1435-5

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.