Macrophage inflammatory protein 3α transgene attracts dendritic cells to established murine tumors and suppresses tumor growth
Toshiaki Fushimi, Akira Kojima, Malcolm A.S. Moore, Ronald G. Crystal
Toshiaki Fushimi, Akira Kojima, Malcolm A.S. Moore, Ronald G. Crystal
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Macrophage inflammatory protein 3α transgene attracts dendritic cells to established murine tumors and suppresses tumor growth

Abstract

Dendritic cells (DCs) are powerful antigen-presenting cells that function as the principal activators of T cells. Since the human CC chemokine, macrophage inflammatory protein 3α (MIP-3α), is chemotactic for DCs in vitro, we hypothesized that adenovirus-mediated gene transfer of MIP-3α (ΑdMIP-3α) to tumors might induce local accumulation of DCs and inhibit growth of preexisting tumors. AdMIP-3α directed expression of mRNA and protein in vitro, and the supernatant of A549 cells infected with AdMIP-3α was chemotactic for DCs. In vivo, injection of AdMIP-3α into subcutaneous tumors resulted in local expression of the MIP-3α cDNA and in the local accumulation of DCs. In four syngeneic tumor models, growth of established tumors was significantly inhibited compared with untreated tumors or tumors injected with control vector, and in all but the poorly immunogenic LLC carcinoma model, this treatment increased survival advantage of the preexisting tumors. In all four tumor models, intratumoral injection of AdMIP-3α induced the local accumulation of CD8b.2+ cells and elicited tumor-specific cytotoxic T-lymphocyte activity, and adoptive transfer of splenocytes of animals receiving this treatment protected against a subsequent challenge with the identical tumor cells. In wild-type but not in CD8-deficient mice, AdMIP-3α inhibited the growth of tumors. Finally, AdMIP-3α also inhibited the growth of distant tumors. This strategy may be useful for enlisting the help of DCs to boost anti-tumor immunity against local and metastatic tumors without the necessity of ex vivo isolation and manipulation of DCs.

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Toshiaki Fushimi, Akira Kojima, Malcolm A.S. Moore, Ronald G. Crystal

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Effects of AdMIP-3α administration on progression of preexisting subcuta...
Effects of AdMIP-3α administration on progression of preexisting subcutaneous tumors. (a–d) Tumor growth. (a) Effects of AdMIP-3α on CT26.CL25 tumor progression. Balb/c mice were injected subcutaneously on day 0 with 3 × 105 CT26.CL25 tumor cells. Six days later, 5 × 108 pfu (in 100 μL) AdMIP-3α (filled triangle) or AdNull (open square) were injected intratumorally; naive animals were used as a further control (open circle). Tumor size was monitored three times each week. (b) Effects of AdMIP-3α administration on the progression of CT26 tumors in Balb/c mice. The experiments (and symbols) were similar to those in a except mice were injected on day 0 with 3 × 105 CT26 colon carcinoma cells, and 8 days later, 5 × 108 pfu AdMIP-3α or AdNull (100 μL) was administered. (c) Same as b (including symbols), but with B16 melanoma cells in C57Bl/6 mice (3 × 105 cells injected subcutaneously at day 0, vectors administered at day 8). (d) Same as b, but with LLC cells in C57Bl/6 mice (3 × 105 cells injected subcutaneously at day 0, vectors administered at day 8). In a–d, the arrow indicates the time of vector administration. ATumor growth significantly inhibited (P < 0.05) in the AdMIP-3α–treated group compared with all controls (AdNull or naive). (e–h) Survival. The survival data are derived from the same animals as in a–d. (e) CT26.CL25 tumors, Balb/c mice. (f) CT26 tumors, Balb/c mice. (g) B16 tumors, C57Bl/6 mice. (h) LLC carcinoma, C57Bl/6 mice.