The CC Chemokine CKβ-11/MIP-3β/ELC/Exodus 3 Mediates Tumor Rejection of Murine Breast Cancer Cells Through NK Cells

Abstract

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-GM1 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.

CCL19 (ELC) as an adjuvant for DNA vaccination: induction of a TH1-type T-cell response and enhancement of antitumor immunity

“…An increase of humoral as well as cellular immunity against HSV was demonstrated. Furthermore, there have been reports in mice showing that CCL19-transfected tumor cells lead to retardation in tumor growth 20,21 and that intratumoral/ intranodal injection of recombinant CCL19 elicits IFN-gdependent systemic anti-tumor responses in a mouse lung cancer model. 22,23 Interestingly, the latter studies describe an increased influx of CD8 þ and CD4 þ T cells as well as DC into tumor sites of CCL19-treated mice.…”

Macrophage-derived chemokine gene transfer results in tumor regression in murine lung carcinoma model through efficient induction of antitumor immunity

“…34 The expression of MIP-3␤/ELC(CK␤-11) in a breast cancer cell line mediated rejection of the transduced tumor. 35 Adenovirusmediated gene transfer of MIP-3␣ to tumors induced local accumulation of DC and inhibited growth of preexisting tumors. 36 MDC is a potent chemoattractant for DC, NK cells, Th2 and Tc2 subsets of T cells.…”

Enhanced expression of Duffy antigen receptor for chemokines by breast cancer cells attenuates growth and metastasis potential

“…Interleukin-13 receptor (IL-13R) overexpression profoundly inhibited MDA-MB-231 tumor in athymic nude mice, but no difference in vitro growth was found between the transfected cells and mock cells (Kawakami et al, 2001). These phenomenon also exist for many chemokines, such as CCL16 (liverexpressed chemokine, LEC) (Giovarelli et al, 2000) and CCL19 (EBI1-ligand chemokine, ELC) (Braun et al, 2000).…”