Abstract 1965: Inhibiting the CCR2/MCP-1 chemokine pathway blocks MDSC recruitment and promotes anti-tumor immunity
Authors: Mittal Payal , Wang Liqing , Akimova Tatiana , Leach Craig A. , Clemente Jose C. , Sender Mathew , Chen Yao , Turenen Brandon , Hancock Wayne W. 
Published: August 2019

Abstract
Host anti-tumor immunity, including the actions of cytotoxic T cells, plays a key role in curtailing the growth of “hot” tumors but can be hindered by multiple mechanisms. One such mechanism involves the local recruitment and expansion of myeloid derived suppressor cells (MDSCs) within the tumor microenvironment. We investigated the role of the CCR2/MCP-1 axis in MDSC-associated tumor progression using the TC1 lung tumor cell line implanted into syngeneic C57BL/6 mice. Phenotypic profiling of TC1 tumors revealed maximal expression of CCR2 by tumor resident MDSCs (p&lt;0.01 vs. neutrophils, tumor-associated macrophages/TAM or T cells), and MCP-1 by transplanted tumor cells (p&lt;0.01 vs. all types of leukocytes), respectively. Additionally, utilization of CCR2 knockout (CCR2KO) mice showed the dependence of progression of TC1 tumor on CCR2 signaling (p&lt;0.01). Tumors in CCR2KO mice had fewer CCR2lowMDSCs (p&lt;0.01), CD4 T cells (p&lt;0.01), and Foxp3+ Treg cells (p&lt;0.05). Conversely, CD8 T cell infiltration was significantly augmented in tumors from CCR2KO mice (p&lt;0.05), and these CD8 T cells were capable of making higher levels of IFN-γ (p&lt;0.01) and granzyme-B (p&lt;0.05) upon restimulation than CD8 T cells from WT tumor-bearing mice. These effects were tumor-specific and not the result of genetic ablation of CCR2 on T cells, since the adoptive transfer of WT or CCR2KO cells into B2D6/F1 mice showed that CCR2KO cells had comparable activation, proliferation, inflammatory cytokine production, and Treg-mediated suppressive function as WT cells (all p&gt;0.05). We next used a thioglycolate-induced peritonitis model of inflammation to validate the role of CCR2 and MCP-1 in trafficking of CCR2+ cells to the site of inflammation. We showed the ability of a CCR2 antagonist to inhibit trafficking of CCR2+ cells to the site of inflammation, in a dose-dependent manner, with a maximal effect at a dose of 10 mg/kg (p&lt;0.05). We then tested the compound at this inhibitory concentration for its ability to impair CCR2+ cell recruitment to MCP-1 expressing TC1 tumors. Use of the CCR2 antagonist blocked growth TC1 tumors (p&lt;0.001) and markedly suppressed intratumoral MDSC numbers (p&lt;0.01), while boosting the numbers of cytotoxic CD8 T cells (p&lt;0.005) and intratumoral expression of IFN-γ, TNF-α, granzyme-B and perforin (all p&lt;0.01). In summary, fully complementary genetic and pharmacologic data indicate that CCR2 targeting may be an important new component of immuno-oncology based therapies.
Note: This abstract was not presented at the meeting.
Citation Format: Payal Mittal, Liqing Wang, Tatiana Akimova, Craig A. Leach, Jose C. Clemente, Mathew Sender, Yao Chen, Brandon Turenen, Wayne W. Hancock. Inhibiting the CCR2/MCP-1 chemokine pathway blocks MDSC recruitment and promotes anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1965.