Tumor vaccination that enhances antitumor T-cell responses does not inhibit the growth of established tumors even in combination with interleukin-12 treatment: the importance of inducing intratumoral T-cell migration.
Interleukin-12 (IL-12) treatment is effective in the CSA1M but not in the Meth A and CSA1M-variant tumor models. The authors investigated the cause by which IL-12 treatment fails to induce tumor regression in these two tumor models. T cells from CSA1M-bearing mice have high levels of IL-12 responsiveness, whereas cells from Meth A-bearing mice display marginal levels of responsiveness. Because IL-12 responsiveness in T cells is induced after T-cell receptor stimulation, the lack of IL-12 responsiveness suggests that T cells in Meth A-bearing mice are not sensitized to Meth A tumor antigen. Immunization of normal mice with attenuated Meth A tumor cells resulted in a protective immunity, as shown by the rejection of challenged viable Meth A cells. Such an immunization, when performed in Meth A-bearing mice, induced potent IL-12 responsiveness in T cells. Nevertheless, IL-12 treatment in these mice did not inhibit tumor growth. In another IL-12-incurable (CSA1M-variant) model, IL-12 responsiveness was observed before tumor cell immunization. However, IL-12 treatment was ineffective regardless of whether tumor cell immunization was performed. In these two models, the failure of IL-12 treatment to induce tumor regression was associated with the lack of T-cell migration to tumor sites. These results indicate that the sensitization of T cells to tumor antigens and generation of IL-12 responsiveness are insufficient to induce tumor regression when these sensitized T cells are not allowed to migrate to tumor sites.
Gao
P
P
Department of Oncology, Biomedical Research Center, Osaka University Graduate School of Medicine, Suita, Japan.
Uekusa
Y
Y
Nakajima
C
C
Iwasaki
M
M
Nakahira
M
M
Yang
Y F
YF
Ono
S
S
Tsujimura
T
T
Fujiwara
H
H
Hamaoka
T
T
D000818:Animals; D000951:Antigens, Neoplasm / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002455:Cell Division; D003131:Combined Modality Therapy; D005354:Fibrosarcoma / Q000276:immunology* / Q000473:pathology; D006649:Histocompatibility Antigens / Q000627:therapeutic use; D007155:Immunologic Factors / Q000627:therapeutic use; D018664:Interleukin-12 / Q000627:therapeutic use*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D006649:Histocompatibility Antigens; D007155:Immunologic Factors; C029237:tumor-associated transplantation antigen; D018664:Interleukin-12