Formalin-fixed tumor cells effectively induce antitumor immunity both in prophylactic and therapeutic conditions.
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 PA28alpha-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-gamma production in splenic lymphocytes, and activation of dendritic cells.


RESULTS
Fixed cells directly induced production of tumor necrosis factor-alpha 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-gamma in response to melanoma cells. Furthermore, this combined treatment showed antitumor immunity initiated by CD8+ and CD4+ T cells in the therapeutic experiments. PA28alpha/beta 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.


CONCLUSIONS
These results suggest that formalin-fixed autologous melanoma cells have a potential to function as effective antigen sources for immunotherapy.
Obata
Chikage
C
Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. cobata@dermatol.med.kyushu-u.ac.jp
Zhang
Manxin
M
Moroi
Yoichi
Y
Hisaeda
Hajime
H
Tanaka
Keiji
K
Murata
Shigeo
S
Furue
Masutaka
M
Himeno
Kunisuke
K
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D016923:Cell Death / Q000276:immunology; D005260:Female; D005404:Fixatives; D005557:Formaldehyde; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology; D008545:Melanoma / Q000276:immunology* / Q000517:prevention & control* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000235:genetics; D012878:Skin Neoplasms / Q000276:immunology* / Q000517:prevention & control* / Q000628:therapy; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014407:Tumor Cells, Cultured
D019496:Cancer Vaccines; D005404:Fixatives; D011506:Proteins; D018664:Interleukin-12; D005557:Formaldehyde; D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex; C486213:Psme1 protein, mouse