Formalin-fixed tumor cells effectively induce antitumor immunity both in prophylactic and therapeutic conditions

• Published in: Journal of dermatological science 2004-05, Vol.34 (3), p.209-219
• Main Authors: Obata, Chikage, Zhang, Manxin, Moroi, Yoichi, Hisaeda, Hajime, Tanaka, Keiji, Murata, Shigeo, Furue, Masutaka, Himeno, Kunisuke
• Format: Article
• Language: English
• Subjects: Animals; Bone Marrow Cells - cytology; Bone Marrow Cells - immunology; Cancer Vaccines - immunology; Cancer Vaccines - pharmacology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - immunology; Cell Death - immunology; Dendritic cells; Female; Fixatives; Formaldehyde; Formalin; Immunotherapy; Interferon-gamma - metabolism; Interleukin-12; Interleukin-12 - immunology; Melanoma - immunology; Melanoma - prevention & control; Melanoma - therapy; Mice; Mice, Inbred C57BL; Mice, Knockout; PA28; Proteasome Endopeptidase Complex; Proteins - genetics; Skin Neoplasms - immunology; Skin Neoplasms - prevention & control; Skin Neoplasms - therapy; Spleen - cytology; Spleen - immunology; Tumor; Tumor Cells, Cultured
• ISSN: 0923-1811; 1873-569X
• DOI: 10.1016/j.jdermsci.2004.02.003

Background : Autologous whole tumor cell-based vaccinations would seem to be ideal since such vaccinations, in contrast to vaccination with a single defined antigen, have the potential to elicit a broad type of T-cell immune response to tumor-associated antigens. Objective : We modified formaldehyde (formalin)-fixed mouse melanoma cells and investigated the utility of those cells as sources of tumor antigens for immunotherapy. Methods : C57BL/6 or the proteasome activator PA28α-knockout mice were intradermally inoculated with 1% formalin-fixed B16 cells three times at weekly intervals either before or after tumor challenge. Simultaneously, interleukin-12 gene was transferred into the skin around immunization sites using gene gun technology. The effects were evaluated by tumor growth, antigen-specific interferon-γ production in splenic lymphocytes, and activation of dendritic cells. Results : Fixed cells directly induced production of tumor necrosis factor-α in dendritic cells more effectively than did frozen and thawed cells. More than 60% of the mice immunized with fixed cells and interleukin-12 rejected the challenged B16 tumor. CD4 + T cells from those mice produced a significant amount of interferon-γ in response to melanoma cells. Furthermore, this combined treatment showed antitumor immunity initiated by CD8 + and CD4 + T cells in the therapeutic experiments. PA28α/β appeared not to be required for the development of CD8 + T cells, although it is known to be essential for the development of CD8 + T cells specific for tyrosinase-related protein-2, one of melanocyte-lineage differentiated antigens. Conclusion : These results suggest that formalin-fixed autologous melanoma cells have a potential to function as effective antigen sources for immunotherapy.