Local delivery of recombinant vaccinia virus expressing secondary lymphoid chemokine (SLC) results in a CD4 T-cell dependent antitumor response.
Secondary lymphoid chemokine (SLC) attracts mature dendritic cells (DCs) and naïve T cells. Co-localization of these cells within local tumor environments may enhance the induction of tumor-specific T cells. However, the presence of danger signals or other DC maturation signals are required to optimize T-cell priming. We hypothesized that expression of SLC in vaccinia virus would provide local chemokine delivery and adjuvant factors. A recombinant vaccinia virus expressing murine SLC (rVmSLC) was constructed and characterized. SLC expression was confirmed by Western blot analysis and functional activity was determined by in vitro chemotaxis assay. Supernatants from rVmSLC-infected cells attracted CD4 T cells, and also induced the migration of CD8 T cells and DCs. Although poxviruses are known to express several chemokine-binding proteins, systemic injection of rVmSLC was well tolerated in mice up to a dose of 1 x 10(7) pfu and did not significantly alter vaccinia-specific T-cell immunity. Local injection of rVmSLC into established tumors derived from the murine colon cancer line, CT26, resulted in enhanced infiltration of CD4 T cells, which correlated with inhibition of tumor growth. The central role of CD4 T cells was further demonstrated by loss of anti-tumor activity in CD4 T-cell depleted mice. Intratumoral delivery of SLC using a poxviral vaccine extends the use of SLC in anti-tumor therapies and may present an effective alternative for improving the immunotherapy of cancer alone or in combination with other anti-tumor agents for clinical therapy.
Flanagan
Kenneth
K
Department of Pathology, Columbia University, 177 Fort Washington Avenue, MHB 7-SK, New York, NY 10032, USA.
Glover
Robert T
RT
Hörig
Heidi
H
Yang
Wancai
W
Kaufman
Howard L
HL
D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics* / Q000276:immunology*; D002460:Cell Line; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000235:genetics*; D002634:Chemotaxis, Leukocyte; D003110:Colonic Neoplasms / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008845:Microinjections; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics* / Q000276:immunology*; D014765:Viral Vaccines / Q000009:adverse effects / Q000235:genetics* / Q000276:immunology*
D019496:Cancer Vaccines; C515479:Ccl21c protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; D014614:Vaccines, Synthetic; D014765:Viral Vaccines