| CCL21 (SLC/TCA4) attracts mature dendritic cells (DCs) and naive T cells. Colocalization of these cells within local tumor environments may enhance the activation 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 CCL21 in vaccinia virus would provide local chemokine delivery as well as adjuvant. A recombinant vaccinia virus encoding murine CCL21 (rVmCCL21) was constructed and characterized. CCL21 expression was confirmed by Western blot analysis and functional activity was determined by in vitro chemotaxis assay. Supernatants from rVmCCL21-infected cells attracted CD4+ and CD8 + T cells. Local injection of rVmCCL21 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 CCL21 using a poxviral vaccine extends the use of CCL21 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.; Full activation and differentiation of T cells depends on signals delivered by costimulatory molecules that mediate T cell proliferation, differentiation and cytokine release. Herein, we demonstrate that CCL21 costimulates expansion of CD4+ and CD8+ T cells and induces Th1 polarization. The costimulatory effects of CCL21 were specific for naive T cells, as CD4+CD25+ regulatory T cells were hyporesponsive to CCL21 induced migration, and unresponsive to CCL21 costimulation. These unique functions of CCL21 to both attract naive T cells as well as costimulate their proliferation and differentiation, suggests that CCL21 is a pivotal molecule for priming T cell responses. |
