| Summary: | <p>Despite expressing antigens that can induce immune surveillance and immune eradication, tumours demonstrate the capacity to evade anti-tumour immunity. Recently, this has been attributed to the ability of tumours to induce a local immunosuppressed micro-environment, which is a major obstacle to successful natural and vaccine induced anti-tumour immunity. Soluble factors such as transforming growth factor beta (TGF&), and interleukin 10 (IL-10), released by cancer and stromal cells, are thought to play a significant role in this local immunosuppression.</p> <p>In order to assess the influence of antagonising these soluble factors locally on tumour biology and tumour immunity, a murine CT26 colorectal carcinoma model that can express cytokine antagonists under Doxycycline (Dox) control was engineered. Two stable CT26 cell lines expressing Dox-inducible soluble extracellular domain of TGF& receptor II (STGF&RII;) or soluble extracellular domain of IL-10 receptor (SIL-10R), were established. Expression of STGF&RII; <em>in vitro</em> and <em>in vivo</em> was only evident after Dox treatment. When Dox was administered directly following subcutaneous (s.c.) inoculation of STGF&RII-expressing; CT26 cells into Balb/c mice, tumour growth was significantly suppressed. Interestingly, inducing STGF&RII; in well-established tumours showed less suppression of tumour growth. To assess the effect of expressing STGF&RII; on tumour immunity the RNA expression of 22 common cytokines was measured in the tumours of mice receiving Dox and control mice. The levels of some of these cytokines were modulated by STGF&RII; expression (e.g TGF&,Tnfsf9, IL-2). We also tested for any additive effect between expressing STGF&RII;, and the administration of anti-CTLA-4 antibody on tumour growth, and tumour immunity.</p> <p>The model described here could help address various limitations seen previously in studies of TGF& blockade. It provides means of effective local antagonism, and it addresses immunological endpoints which have been limited in previous studies. Because of its tight regulation, the model also allows identification of the best timing of TGF& blockade alone or in combination with other immunotherapeutics.</p>
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