Gene-modified tumor vaccine with therapeutic potential shifts tumor-specific T cell response from a type 2 to a type 1 cytokine profile.
Vaccination with a poorly immunogenic/nonimmunogenic tumor fails to protect the host from a subsequent challenge with the same tumor. The mechanisms underlying the failure of these tumors to sensitize therapeutic T cells are not clearly understood, but the inability of host T cells to recognize tumor has been implicated. In this study, vaccination with the poorly immunogenic B16BL6-D5 (D5 H-2b) tumor fails to generate therapeutic T cells from the tumor vaccine-draining lymph nodes (TVDLN) in our adoptive immunotherapy model. However, if vaccination is performed with an allogeneic MHC class I gene (H-2 Kd)-modified tumor, the T cells obtained from the TVDLN are therapeutic after activation with anti-CD3 and IL-2. Lymph nodes (LN) draining both D5 and D5-Kd tumor vaccines contained increased numbers of cells with reduced expression of L-selectin (L-selectin(low/-)) compared with naive LN. This implies that vaccination led to sensitization of T cells even in LN draining the unmodified D5 tumor. L-selectin(low/-) cells from D5-Kd, but not D5, TVDLN were therapeutic in our animal model. No antitumor activity was seen in the high level L-selectin T cells. L-selectin(low/-) T cells exhibited tumor-specific cytokine release that was type 2 (IL-4, IL-10) following vaccination with native D5 and type 1 (IFN-gamma) following vaccination with gene-modified D5-Kd. Our data suggest that the failure of unmodified D5 to generate therapeutic T cells is not due to an inability to recognize tumor Ags, but, rather, to the induction of an immune response that is ineffective in mediating tumor regression, i.e., immune deviation.
Hu
H M
HM
The Robert W. Franz Cancer Research Center, The Earle A. Chiles Research Institute, Portland, OR 97213, USA.
Urba
W J
WJ
Fox
B A
BA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics* / Q000276:immunology*; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis*; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology; D005260:Female; D005805:Genes, MHC Class I / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods; D007376:Interleukin-2 / Q000494:pharmacology; D019041:L-Selectin / Q000096:biosynthesis; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D014407:Tumor Cells, Cultured; D019444:Vaccines, DNA / Q000276:immunology*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D019496:Cancer Vaccines; D016207:Cytokines; D007376:Interleukin-2; D019444:Vaccines, DNA; D019041:L-Selectin