Potent antitumor activity of interleukin-27.

Over recent years advances in surgical intervention, radiation therapy and chemotherapy have improved overall cancer care. The prevention of tumor invasion, metastasis and recurrence has not however significant progressed. Many currently available therapeutics remain associated with debilitating side-effects and the development of treatment resistance remains a considerable problem. In 2002 nearly 1,285,000 new cancer cases were diagnosed in the United States, and due to the lack of options for the treatment of advanced disease more than 550,000 Americans died of the disease.

Immunotherapy represents an emerging approach to the treatment of cancer that promises high specificity with negligible side effects. This approach to cancer treatment commonly involves the stimulation of T cells and antibody production and the use of cytokines has been extensively studied.

Interleukin (IL)-12 is one immunotherapeutic candidate that held early promise. This proinflammatory and immunoregulatory cytokine plays a central role in the interaction between innate resistance and adaptive immunity by inducing IFN-gamma production and generating T helper cell 1 (Th1) responses and cytotoxic T lymphocytes (CTLs). In several studies comparing different cytokines, IL-12 was the most effective in terms of tumor eradication, anti-metastatic activity, and eliciting long-term antitumor immunity. Clinical trials have however demonstrated that excessive toxicity limits the clinical application of IL-12. Therefore, local and efficient expression of IL-12 or harnessing the anticancer properties of other cytokines is being investigates as an alternative immunotherapeutic approach.

In their recent Cancer Research paper, Hasada et al evaluate the anticancer potential of IL-27. This recently identified IL-12 family member is a heterodimeric cytokine that is produced early after activation by antigen presenting cells. IL-27 binds to an orphan receptor designated T cell cytokine receptor (also known as WSX-1), a receptor that is similar to the IL-12 receptor beta2 subunit. Receptor binding induces the proliferation of naive CD4+T cells and the initiation of a Th1 response. IL-27 induces expression of the IL-12 receptor that in turn allows the Th1 response to be maintained. The close relationship between IL-12 and IL-27 is synergistic in nature.

Hisada et al evaluated the in vivo activity of IL-27 in a murine model of colonic carcinoma. This group found that while tumors continued to grow in mice throughout the 25 day experimental period under control conditions, growth was negligible for cancer cells transfected with IL-27. INF-gamma production by spleen cells from mice inoculated with IL-27 transfected cells was considerable increased and the cytotoxic activity of these spleen upon re-exposure to the cancer cells was also dramatically enhanced. Furthermore when injected into mice that had previously been inoculation with IL-27 transfected colon cancer cells, non-transfected cancer cells failed to develop into tumors suggesting protective immunity.

These exciting data suggest that IL-27 expression may be able to limit tumor growth and to prevent reoccurrence. Since IL-27 regulates the initiation of TH1 responses, contrasting with IL-12 which acts down-stream to maintain these responses, targeting IL-27 may be an effective approach to immunotherapeutics that lacks the adverse events associated with IL-12. The comparative lack of adverse effects has indeed been demonstrated in the mouse. Further study of IL-27 is therefore eagerly awaited.

Entry date Sunday, August 29, 2004

Adapted from Hisada et al, Cancer Res. 2004 Feb 1;64(3):1152-6.