title: Tumour-induced polarization of tumour vaccine-draining lymph node T cells to a type 1 cytokine profile predicts inherent strong immunogenicity of the tumour and correlates with therapeutic efficacy in adoptive transfer studies.
abstract: Previously we have shown that vaccination with the poorly immunogenic B16BL6-D5 melanoma (D5) elicits a dominant type 2 (T2) cytokine response that fails to protect the host from a subsequent tumour challenge. Here we investigated whether the inherent immunogenicity of a tumour can be correlated with its ability to bias the anti-tumour cytokine response towards either a type 1 (T1) or a T2 profile. The immune response to six tumours of different inherent immunogenicity was assayed. By isolating l-selectinlow T cells from tumour vaccine draining lymph nodes (TVDLN), it was possible to detect tumour-specific cytokine responses from both immunogenic, poorly immunogenic and non-immunogenic tumours. Immunogenic tumours (MCA-304, MCA-309, MPR-4) induced a predominant tumour-specific T1 cytokine response. In contrast, weakly (MCA-310, MPR-3) and poorly/non-immunogenic tumours (MPR-5, D5) sensitized T cells with a predominant tumour-specific T2 cytokine response. A significant correlation (P < 0.025) between immunogenicity and the ratio of tumour-specific interferon-gamma : interleukin-4 (IL-4) secretion by TVDLN T cells was identified. We then documented that non-therapeutic T cells primed by the poorly immunogenic D5, recognized "tumour-rejection" antigens and that reprogramming their cytokine response, by in vitro culture with IL-12 and anti-IL-4, to a T1 profile uncovered therapeutic efficacy. In contrast, TVDLN T cells primed by a therapeutic vaccine lose therapeutic efficacy when cultured with IL-4. These results provide insights into the development of a protective anti-tumour immune response and strengthen the hypothesis that a T1 cytokine response is critical for T-cell-mediated tumour regression.
authors.affiliation: Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA.
authors.forename: Hauke
authors.initials: H
authors.lastname: Winter
authors.forename: Hong-Ming
authors.initials: HM
authors.lastname: Hu
authors.forename: Christian H
authors.initials: CH
authors.lastname: Poehlein
authors.forename: Erik
authors.initials: E
authors.lastname: Huntzicker
authors.forename: John J
authors.initials: JJ
authors.lastname: Osterholzer
authors.forename: Jaffar
authors.initials: J
authors.lastname: Bashy
authors.forename: David
authors.initials: D
authors.lastname: Lashley
authors.forename: Bruce
authors.initials: B
authors.lastname: Lowe
authors.forename: Jane
authors.initials: J
authors.lastname: Yamada
authors.forename: Gregory
authors.initials: G
authors.lastname: Alvord
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Urba
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Fox
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D007108:Immune Tolerance; D016219:Immunotherapy, Adoptive; D015847:Interleukin-4 / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000517:prevention & control; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D019496:Cancer Vaccines; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4