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

作者：Salerno Elise P; Shea Sofia M; Olson Walter C; Petroni Gina R; Smolkin Mark E; McSkimming Chantel; Chianese Bullock Kimberly A; Slingluff Craig L Jr^*

来源：Cancer Immunology, Immunotherapy, 2013, 62(7): 1149-1159.

DOI：10.1007/s00262-013-1435-5

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

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 na < ve 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 alpha E beta 7 and alpha 1 beta 1 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-gamma production in response to peptide stimulation and few tetramer(pos) cells producing IFN-gamma. 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.

• 出版日期2013-7