Acta Pharmacologica Sinica (2009) 30: 637-645; doi: 10.1038/aps.2009.44

Aim: Flt4 plays a key role in promoting tumor metastasis by stimulating solid tumor lymphangiogenesis.  In this study, mouse Flt4 (mFlt4) was displayed on T4 phage in order to explore the feasibility of breaking immune tolerance to “self-antigens?and to evaluate the phage’s antitumor activity.

Methods: A T4 phage nanometer particle expressing mFlt4 on the surface was constructed for evaluation as a recombinant vaccine.  The presence of the mFlt4 gene in the T4-mFlt4 recombinant vaccine was verified by PCR and Western blot analysis.  The immunotherapeutic potential of T4-mFlt4 was tested in mice injected with Lewis lung carcinoma (LLC) cells.  Anti-Flt4 antibody producing B cells were detected by ELISPOT.  The effects of T4-mFlt4 on lymphatic metastasis and lymphangiogenesis were investigated in a mouse antimetastasis assay and by Flt4 and CD105 immunohistochemistry.

Results: The T4-mFlt4 recombinant vaccine demonstrated antitumor activity and elicited autoantibodies against mFlt4.  Mice carrying LLC-derived tumors exhibited prolonged survival when given the vaccine compared with control-treated animals.  The vaccine also inhibited lymphangiogenesis and tumor metastasis in the mouse models.  However, T4-mFlt4 was not observed to inhibit tumor growth.

Conclusion: The T4-mFlt4 recombinant vaccine induced protective antitumor immunity and antimetastasis against LLC.  Induction of an autoimmune response directed against tumor progression merits further study as a new strategy for immunotherapy in cancer.

Keywords: Flt4; self-immunization; cancer therapy; T4 bacteriophage