CCR7 regulates B16 murine melanoma cell tumorigenesis in skin

Tumor cell-associated chemokine receptors play distinct roles in cancer biology, including enhancement of lymph node (LN) metastasis. To determine if CCR7 influences tumor formation in skin, we inoculated B16 cells transduced with CCR7 and luciferase (CCR7-luc-B16) or with retroviral vector and luciferase (pLNCX2-luc-B16) into ear skin and footpads of wild-type (WT) mice. In contrast to pLNCX2-luc-B16 cells, 97% of CCR7-luc-B16 cell-inoculated mice formed skin tumors as well as cervical LN metastases by Day 21 following ear inoculation. CCR7-expressing and control B16 cells, however, formed tumors of similar size and with high-efficiency in SCID-beige mice. Cells from both lines accumulated in the skin of WT mice in similar numbers until Day 7. By Day 11, however, control cells decreased tenfold, whereas CCR7-luc-B16 cells formed small tumor nodules. Tumor cells were infrequently detected in draining cervical LNs up to 11 days after injection of both cell lines, but stable nodal metastases were only observed after CCR7-luc-B16 ear tumors had been established (∼Day 21). ELISPOT assays revealed that IFN-γ-producing cells in draining LNs from CCR7-luc-B16-injected ears were reduced through Day 7. After footpad injection, tumor formation by CCR7-expressing B16 cells was enhanced only with small, initial tumor cell inocula. With larger inocula, tumor formation was equivalent, but the numbers of tumor-infiltrating leukocytes were reduced by approximately sixfold in CCR7-B16 tumors compared with pLNCX2-B16 tumors of equal size. IFN-γ and CXCL10 were reduced 35- and sixfold, respectively, in CCR7-B16 cell tumors (vs. control tumors). Thus, CCR7 expression enhances tumorigenesis in addition to facilitating LN metastasis.