The development of peritumoral stroma required for IL-12 induced tumor regression depends on the T cell/IFN-gamma-involving host-tumor interaction.
T cell migration into tumor masses is a critical process in the scenario of IL-12-induced tumor regression. Our previous study showed that this depends on the development of peritumoral stroma prior to IL-12 therapy. The present study investigated the regulation of the development of peritumoral stroma in comparison with tumor-parenchymal stroma. In the OV-HM and CSA1M tumor models, tumor regression associated with T cell migration was induced following IL-12 treatment. Both OV-HM and CSA1M tumor masses growing in syngeneic mice developed peritumoral stroma before IL-12 treatment. However, peritumoral stroma was not observed in these two types of tumor masses generated in nude mice, T cell-depleted syngeneic mice, anti-IFN-gamma mAb-treated mice or IFN-gamma-deficient mice. In contrast, parenchymal stroma formation did not appear to be affected because tumors generated in these groups of mice exhibited rather higher growth rates than those of tumors in normal syngeneic mice. Importantly, the lack of peritumoral stroma in tumor masses was associated with the failure of T cells to migrate to these tumor masses: splenic T cells prepared from IL-12-treated tumor-bearing mice migrated into the corresponding tumor mass growing in untreated syngeneic recipient mice, whereas portions of the same donor cells failed to migrate into the above stroma-negative tumor masses. These results indicate that the development of peritumoral and parenchymal stroma is differentially regulated; there exist functional differences in the two types of stroma; and the formation of peritumoral stroma requires components of the host's immune system such as IFN-gamma and T cells.
Uekusa
Y
Y
Department of Oncology, Biomedical Research Center, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Ogawa
M
M
Gao
P
P
Iwasaki
M
M
Ono
S
S
Tsujimura
T
T
Nakazawa
M
M
Sakuda
M
M
Clancy
B
B
Fujiwara
H
H
Hamaoka
T
T
D000818:Animals; D003238:Connective Tissue / Q000502:physiology*; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D007371:Interferon-gamma / Q000502:physiology*; D018664:Interleukin-12 / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000502:physiology*; D014407:Tumor Cells, Cultured; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology
D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D018664:Interleukin-12; D007371:Interferon-gamma