title: Activation, dysfunction and retention of T cells in vaccine sites after injection of incomplete Freund's adjuvant, with or without peptide.
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.
authors: Division of Surgical Oncology, Department of Surgery, University of Virginia, Charlottesville, VA, USA.
authors: Elise P
authors: EP
authors: Salerno
authors: Sofia M
authors: SM
authors: Shea
authors: Walter C
authors: WC
authors: Olson
authors: Gina R
authors: GR
authors: Petroni
authors: Mark E
authors: ME
authors: Smolkin
authors: Chantel
authors: C
authors: McSkimming
authors: Kimberly A
authors: KA
authors: Chianese-Bullock
authors: Craig L
authors: CL
authors: Slingluff
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D005260:Female; D005620:Freund's Adjuvant / Q000008:administration & dosage / Q000276:immunology*; D006801:Humans; D039222:Integrin alpha1beta1 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008055:Lipids / Q000008:administration & dosage / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism; D008875:Middle Aged; D010455:Peptides / Q000276:immunology*; D054367:Receptors, CXCR3 / Q000378:metabolism; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D019496:Cancer Vaccines; D005620:Freund's Adjuvant; D039222:Integrin alpha1beta1; D016023:Integrins; D007371:Interferon-gamma; D037181:Lectins, C-Type; D008055:Lipids; D010455:Peptides; D054367:Receptors, CXCR3; D000099192:CD69 Antigens; C515187:CXCR3 protein, human; C114843:incomplete Freund's adjuvant; C070709:integrin alphaEbeta7
references: J Immunol. 2007 Oct 15;179(8):5033-40
references: 17911588
references: Nat Med. 2004 Sep;10(9):909-15
references: 15340416
references: Cancer Res. 2011 Jan 15;71(2):328-38
references: 21224355
references: N Engl J Med. 2011 Jun 2;364(22):2119-27
references: 21631324
references: Cancer J. 2011 Sep-Oct;17(5):343-50
references: 21952285
references: J Immunol. 2010 Apr 1;184(7):3841-9
references: 20200271
references: J Immunol. 2003 May 1;170(9):4638-48
references: 12707342
references: J Immunol. 2005 Mar 1;174(5):2919-25
references: 15728503
references: J Transl Med. 2010 Aug 20;8:79
references: 20727190
references: Infect Immun. 2003 Jun;71(6):3572-7
references: 12761142
references: Cancer Res. 2009 Aug 1;69(15):6249-55
references: 19638592
references: Clin Cancer Res. 2007 Nov 1;13(21):6386-95
references: 17975151
references: Int J Cancer. 1999 Oct 29;83(3):326-34
references: 10495424
references: Clin Cancer Res. 2009 Nov 15;15(22):7036-44
references: 19903780
references: Nat Med. 2013 Apr;19(4):465-72
references: 23455713
references: Science. 1945 May 4;101(2627):468-9
references: 17799002
references: J Immunother. 2012 Jan;35(1):78-88
references: 22130163
references: J Clin Oncol. 2011 Jul 20;29(21):2924-32
references: 21690475
references: Annu Rev Immunol. 2004;22:745-63
references: 15032595