title: CCL2 blockade augments cancer immunotherapy.
abstract: Altering the immunosuppressive microenvironment that exists within a tumor will likely be necessary for cancer vaccines to trigger an effective antitumor response. Monocyte chemoattractant proteins (such as CCL2) are produced by many tumors and have both direct and indirect immunoinhibitory effects. We hypothesized that CCL2 blockade would reduce immunosuppression and augment vaccine immunotherapy. Anti-murine CCL2/CCL12 monoclonal antibodies were administered in three immunotherapy models: one aimed at the human papillomavirus E7 antigen expressed by a non-small cell lung cancer (NSCLC) line, one targeted to mesothelin expressed by a mesothelioma cell line, and one using an adenovirus-expressing IFN-alpha to treat a nonimmunogenic NSCLC line. We evaluated the effect of the combination treatment on tumor growth and assessed the mechanism of these changes by evaluating cytotoxic T cells, immunosuppressive cells, and the tumor microenvironment. Administration of anti-CCL2/CCL12 antibodies along with the vaccines markedly augmented efficacy with enhanced reduction in tumor volume and cures of approximately half of the tumors. The combined treatment generated more total intratumoral CD8+ T cells that were more activated and more antitumor antigen-specific, as measured by tetramer evaluation. Another important potential mechanism was reduction in intratumoral T regulatory cells. CCL2 seems to be a key proximal cytokine mediating immunosuppression in tumors. Its blockade augments CD8+ T-cell immune response to tumors elicited by vaccines via multifactorial mechanisms. These observations suggest that combining CCL2 neutralization with vaccines should be considered in future immunotherapy trials.
authors.affiliation: Thoracic Oncology Research Laboratory and Department of Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA. gfrid@mail.med.upenn.edu
authors.forename: Zvi G
authors.initials: ZG
authors.lastname: Fridlender
authors.forename: George
authors.initials: G
authors.lastname: Buchlis
authors.forename: Veena
authors.initials: V
authors.lastname: Kapoor
authors.forename: Guanjun
authors.initials: G
authors.lastname: Cheng
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Sunil
authors.initials: S
authors.lastname: Singhal
authors.forename: M Cecilia
authors.initials: MC
authors.lastname: Crisanti
authors.forename: Cecilia
authors.initials: C
authors.lastname: Crisanti
authors.forename: Liang-Chuan S
authors.initials: LC
authors.lastname: Wang
authors.forename: Daniel
authors.initials: D
authors.lastname: Heitjan
authors.forename: Linda A
authors.initials: LA
authors.lastname: Snyder
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D007167:Immunotherapy / Q000379:methods*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D000090204:Mesothelin; D051379:Mice; D018945:Monocyte Chemoattractant Proteins / Q000037:antagonists & inhibitors / Q000276:immunology; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; C491224:Ccl12 protein, mouse; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018945:Monocyte Chemoattractant Proteins; C000715528:Msln protein, mouse; D000090204:Mesothelin