The CC chemokine CKβ-11/MIP-3β/ELC/exodus 3 mediates tumor rejection of murine breast cancer cells through NK cells

CKβ-11 chemoattracts T cells, B cells, dendritic cells, macrophage progenitors, and NK cells and facilitates dendritic cell and T cell interactions in secondary lymphoid tissues. We hypothesized that expression of CKβ-11 in tumor cells may generate antitumor immunity through these interactions. After transduction with the retroviral vector L(CKβ11)SN, the murine breast cancer cell line C3L5 (C3L5-CKβ11) showed expression of retroviral mRNA by Northern analysis and production of functional CKβ-11 by chemotaxis of human NK cells to C3L5-CKβ11 supernatant. Only 10% of mice injected with C3L5-CKβ11 developed tumors, compared with 100% of mice injected with a transduced control C3L5 line (C3L5-G1N). Importantly, the in vitro growth characteristics' of the CKβ-11-transduced cell line were unaffected, suggesting the difference in growth in vivo was a result of chemokine production. Vaccination with C3L5-CKβ11 partially protected animals from parental C3L5 challenge. Immunodepletion with anti-asialo-G(M1) or anti-CD4 during C3L5-CKβ11 vaccination significantly reduced CKβ-11 antitumor activity compared with control and anti-CD8-treated groups. Splenocytes from NK-depleted animals transferred the acquired immunity generated with C3L5-CKβ11 vaccination, while splenocytes from the CD4- depleted animals did not. These results indicate, for the first time, that expression of CKβ-11 in a breast cancer cell line mediates rejection of the transduced tumor through a mechanism involving NK and CD4⁺ cells. Furthermore, CKβ-11-transduced tumor cells generate long-term antitumor immunity that requires CD4⁺ cells. These studies demonstrate the potential role of CKβ-11 as an adjuvant in stimulating antitumor responses.