Expression of the
chemokine receptor CXCR4 by
tumor cells promotes
metastasis, possibly by activating prosurvival signals that render
cancer cells resistant to immune attack. Inhibition of CXCR4 with a
peptide antagonist, T22, blocks metastatic implantation of CXCR4-transduced B16 (CXCR4-luc-B16)
melanoma cells in lung, but not the outgrowth of established
metastases, raising the question of how T22 can best be used in a clinical setting. Herein, whereas the treatment of CXCR4-luc-B16 cells in vitro with the CXCR4
ligand CXCL12 did not reduce killing induced by
cisplatin or
cyclophosphamide, CXCL12 markedly reduced Fas-dependent killing by gp100-specific (pmel-1) CD8(+) T cells. T22 pretreatment restored sensitivity of CXCR4-luc-B16 cells to pmel-1 killing, even in the presence of CXCL12. Two immune-augmenting regimens were used in combination with T22 to treat experimental lung
metastases. First, low-dose
cyclophosphamide treatment (100 mg/kg) on day 5 in combination with T22 (days 4-7) yielded a approximately 70% reduction of B16 metastatic
tumor burden in the lungs compared with
cyclophosphamide treatment alone (P < 0.001). Furthermore, whereas anti-CTL
antigen 4 (CTLA4)
monoclonal antibody (mAb; or T22 treatment) alone had little effect on established B16
metastases, pretreatment with T22 (in combination with anti-CTLA4 mAb) resulted in a 50% reduction in lung
tumor burden (P = 0.02). Thus, in vitro, CXCR4 antagonism with T22 renders B16 cells susceptible to killing by
antigen-specific T cells. In vivo, T22 synergizes with
cyclophosphamide or anti-CTLA4 mAb in the treatment of established lung
metastases, suggesting a novel strategy for augmenting the efficacy of
immunotherapy.