Dias, Sergio; (1998) Molecular and cellular changes in the tumour microenvironment during IL-12 therapy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A murine model of breast carcinoma, HTH-K, derived from a spontaneous tumour in a colony of BALB/c-neu transgenic mice, was established as a transplantable tumour and cell line. HTH-K formed comedo-type, metastatic and highly angiogenic breast carcinomas. The model was further characterised in terms of its cellular infiltrate, cytokine network and the molecular basis for its angiogenic phenotype. HTH-K tumours shared several features with the equivalent human malignancy and were subsequently used to study anti-tumour effects of interleukin-12 (IL-12). Treatment of HTH-K-bearing mice led to tumour regression and cure which was related to the duration of IL-12 treatment. Sequential molecular and phenotypic changes were studied in IL-12 treated tumours. IFN-[gamma] mRNA was detected 8 hours after the first treatment. mRNA expression for the IFN-[gamma] inducible genes [beta]2-microglobulin and indoleamine dioxygenase was subsequently induced, together with the chemokine IP-10. IL-12 treated tumours had an abundant cellular infiltrate, mainly CD8+ T cells, showed a significant reduction in vasculature and had increased apoptotic tumour cells throughout treatment. 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. The anti-angiogenic effects of IL-12 were then studied in detail. VEGF and MMPs were implicated in the angiogenic process in HTH-K, and IL-12 downregulated local production of these proteins. A number of in vitro and in vivo experiments led to the conclusion that IL-12 acted in at least two ways: removal of the pro-angiogenic stimulus and blocking the release and activity of MMPs. The results suggested that IL-12 might be usefully combined with agents such as the inhibitor MMP inhibitor Batimastat (BB-94). When given sequentially for short periods of time, the two agents produced little toxicity and showed similar anti-tumour effects to those seen with prolonged IL-12 therapy. These results suggest that IL-12 may be used with other agents with reduced toxicity but maintenance of its anti-tumour effects.

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