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.