title: Sensitization of B16 tumor cells with a CXCR4 antagonist increases the efficacy of immunotherapy for established lung metastases.
abstract: 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.
authors.affiliation: Dermatology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-1908, USA.
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Lee
authors.forename: Takashi
authors.initials: T
authors.lastname: Kakinuma
authors.forename: Julia
authors.initials: J
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Palmer
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: Sam T
authors.initials: ST
authors.lastname: Hwang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D003520:Cyclophosphamide / Q000008:administration & dosage; D003602:Cytotoxicity, Immunologic; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008546:Melanoma, Experimental / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010455:Peptides / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D010455:Peptides; D019718:Receptors, CXCR4; C516580:T22 peptide; D003520:Cyclophosphamide