NEW IL-1 FAMILY MEMBER ELICITS ANTI-TUMOR IMMUNITY

Several laboratories recently identified new IL-1 and IL-1 receptor family members from EST databases that share sequence similarity with known family members.^1-3 A unifying nomenclature has been adopted for the IL-1 family in which the ten members have been designated IL-1F1 to IL-1F10.² Likewise, IL-1 receptor family members have been assigned the systematic designation IL-1 R1 to IL-1 R9 (Table 1).³ Although no functional information was initially available for the newly identified family members, a recent report implicates one of these orphan proteins in anti-tumor immunity.⁴

IL-1F7 was described by a number of laboratories and consequently was known by many names including IL-1H4, FIL1 zeta, IL-1RP1, and IL-1H.² Several splice variant isoforms have been reported for this protein and these are now designated IL-1F7a - e.⁵ Recent reports have concentrated on the IL-1F7 beta isoform.^3,5,6 This protein is synthesized as a 218 amino acid pro form that is cleaved by caspase-1 to yield a secreted mature form composed of amino acids 21-218.⁶

When tested against a series of IgG Fc fusion proteins, IL-1F7b bound to IL-1 R5 (IL-18 R alpha), but not to IL-1 R1 or IL-1 R4.⁶ Binding was observed for both the pro and mature forms, although the mature form bound with ten-fold higher avidity. This binding affinity, as measured by BIAcore analysis, was much lower (130 nM) than the affinity of IL-1 R5 for IL-18 (2.3 nM). Chemical cross-linking experiments reveal that, in contrast to IL-18, the binding of IL-1F7b to IL-1 R5 fails to recruit the signaling subunit IL-1 R7 (IL-18 R beta). Not surprisingly, IL-1F7b failed to elicit any apparent signaling in IL-18 responsive cells.^5,6 Therefore, it seems likely that additional receptor subunits are involved in IL-1F7b signaling.

As for the function of the IL-1F7b isoform, Gao et al. recently examined its potential as an anti-cancer agent.⁴ A cDNA encoding pro-IL-1F7b was packaged into an adenovirus gene transfer system and injected into established MCA205 fibrosarcoma tumors in C57BL/6 mice. Tumor cells (2 x 10⁵) were introduced on day 0 by intradermal injection. A single injection on day 7 with adenovirus/IL-1F7b significantly retarded tumor growth when compared with a control adenovirus. Multiple injections on days 7, 10, 13, and 16 were even more effective and resulted in complete tumor clearance in several mice. These mice were completely resistant to subsequent challenge with 5 x 10⁵ MCA205 cells.⁴

Adenovirus/IL-1F7b had no anti-tumor effect in nude mice or SCID mice, both of which lack functional T cells and B cells.⁴ Similarly, no anti-tumor effect was observed in mice deficient in IFN-gamma, IL-12 p40, or Fas ligand. IFN-gamma and IL-12 are key cytokines in promoting cellular anti-tumor responses. Fas ligand is known to be essential for the anti-tumor activity of IL-18 which functions independently of IL-12. These results suggest that IL-1F7b may rely on a combination of pathways to elicit anti-tumor immunity. Although the mechanistic details of IL-1F7b activity are still very unclear, this protein appears to have significant anti-tumor activity and possible therapeutic potential.⁴

References

1. Roux-Lombard, P. (1998) Eur. Cytokine Netw. 9:565.
2. Sims, J.E. et al. (2001) Trends Immunol. 22:536.
3. Sims, J.E. (2002) Curr. Opin. Immunol. 14:117.
4. Gao, W. et al. (2003) J. Immunol. 170:107.
5. Bufler, P. et al. (2002) Proc. Natl. Acad. Sci. USA 99:13723.
6. Kumar, S. et al. (2002) Cytokine 18:61.