Multiple molecular and cellular changes associated with tumour stasis and regression during IL-12 therapy of a murine breast cancer model.
IL-12 treatment of a murine transplantable breast carcinoma (HTH-K) led to tumour regression and cure which was related to the duration of treatment. We studied the sequential molecular and phenotypic changes in IL-12-treated tumours. IFN-gamma mRNA was detected 8 hr after the first treatment. mRNA expression for the IFN-gamma-inducible genes beta 2-microglobulin and indoleamine dioxygenase (IDO) was induced subsequently, together with the chemokine IP-10. IL-12-treated tumours had an abundant cellular infiltrate, consisting mainly of CD8+ T cells. mRNA for granzyme B and perforin also could be detected, suggesting that those cells were activated. After 7 days of daily therapy, tumours in IL-12-treated mice had a significant reduction in vasculature. Finally, the number of apoptotic tumour cells increased throughout IL-12 treatment. We compared the anti-tumour effects of IL-12 to those induced by IFN-gamma therapy, which caused initial tumour stasis but subsequent tumour progression. IFN-gamma induced beta 2-microglobulin and IDO over a 7-day period, but IP-10 was induced only transiently. IFN-gamma caused a lesser cellular infiltrate, a minor anti-angiogenic effect and a transient apoptotic effect. The success of IL-12 may be due to its ability to produce a distinct sequence of molecular and phenotypic changes in tumours, leading to an anti-tumour immune response, toxicity against tumour cells and an anti-angiogenic effect. Other cytokines, such as IFN-gamma, induce some, but not all, of these actions. Comparison of IL-12 and IFN-gamma suggests that sustained induction of IP-10 and activation of a resulting cellular infiltrate may be key changes in regressing tumours.
Dias
S
S
Biological Therapies Laboratory, Imperial Cancer Research Fund, London, UK. diassjr@icrf.icnet.uk
Thomas
H
H
Balkwill
F
F
D000818:Animals; D053804:Granzymes; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000627:therapeutic use*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D054353:Perforin; D010641:Phenotype; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology
D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D054353:Perforin; D018664:Interleukin-12; D007371:Interferon-gamma; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases