Augmented antitumor activity of a secondary lymphoid-tissue chemokine (SLC)-interleukin (IL) 2 fusion protein in...

To enhance the antitumor efficacy of IL2 gene therapy, combinations of several other genes, such as p53, a tumor suppressor gene, or lymphotactin, a C-chemokine, and the IL2 gene are attempted, and synergistic effects are observed. We report here on the enhanced antitumor activity of a fusion protein (mSLC-IL2) comprised of a newly identified member of the CC-chemokine family, mouse SLC (mSLC), and mouse IL2 (mIL2).

We constructed mSLC-IL2 by connecting the N-terminus of mIL-2 to the C-terminus of mSLC using a two-amino-acid linker. The resultant fusion protein retained both mIL2 activity, as measured in a standard proliferation assay using a mouse IL-2 dependent cell line, and chemokine activity, as measured in a chemotaxis assay using a preB cell line expressing mSLC-specific receptor, CCR7. The gene encoding mSLC-IL2 was retrovirally transduced into fibroblast CL.7 cells, derived from Balb/c mice.

Intradermal transplantation of fibroblasts expressing mSLC-IL2 into syngenic mice induced a dense accumulation of CD4(+) and CD8(+) cells at the sites of transplantation. Moreover, when CT-26 cells, derived from colon adenocarcinoma cells, were co-transplanted with mSLC-IL2-transduced fibroblasts, the CT-26 cell exhibited significantly lower tumorigenicity than CT-26 cells co-transplanted with mIL2-transduced fibroblasts.

These findings, obtained from both in vitro and in vivo data, suggest that the gene encoding mSLC-IL2 may be a good candidate for inclusion as part of an anticancer gene therapy protocol.