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-α 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.

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…While chronic inflammation may promote tumorigenesis [5,20], the tumor cells themselves also attract immune cells through the secretion of a wide range of chemokines such as IL-8 (CXCL8 in human/CXCL2 in mouse), CCL2 (MCP-1), CCL3 (MIP-1α), CCL5 (RANTES), CXCL6 (huGCP-2), and KC (CXCL1), and cytokines such as IL-1β, IL-6, TNFα, GM-CSF, and G-CSF, thereby inducing inflammation [21][22][23][24][25][26][27][28][29][30][31][32]. Cytokines from tumors may regulate tumor growth or modify the anti-tumor immune responses [33][34][35][36].…”

The Role of Regulatory T Cells in Mesothelioma

“…CCL2, CCL12 and CXCL12 secreted or expressed by tumours cells (including mesothelioma cells) plus other tumour-associated cells also have chemotactic properties for Treg cells [27]. CCL2/CCL12 blockade in a murine AE17 model transfected with human mesothelin was shown to marginally inhibit tumour growth [28]. However, the blockade of CCL2/CCL12 combined with a vaccine targeted at the human mesothelin led to complete tumour clearance in two thirds of the animals treated.…”

Loss of monocyte chemoattractant protein-1 expression delays mammary tumorigenesis and reduces localized inflammation in the C3(1)/SV40Tag triple negative breast cancer model

“…31 Similarly, Fridlander et al, demonstrated a beneficial effect of MCP-1 neutralization in a murine model of non-small cell lung cancer. 32 However, there have been relatively few mechanistic studies to link MCP-1 expression to breast cancer progression, and in particular TNBC. MCP-1 is expressed at relatively low levels in normal mammary epithelial tissue and circulating plasma, but increases dramatically with breast cancer progression.…”