Grossman and Nywening et al. show that in patients with metastatic colorectal cancer, increased preoperative levels of CCR2+ inflammatory monocytes (IMs) were associated with reduced progression-free and overall survival. CCR2+ IMs were recruited to liver metastases via CCL2, which was upregulated in tumors, and once in the tumor, IMs transformed into immunosuppressive tumor-associated macrophages (TAMs). In mice, CCR2 knockout or inhibition reduced TAMs and tumor burden, increased CD8+ and CD4+ effector TILs, and, when combined with chemotherapy, prolonged survival.
The tumor microenvironment (TME) represents a significant barrier to creating effective therapies for metastatic colorectal cancer (mCRC). In several malignancies, bone marrow derived CCR2(+) inflammatory monocytes (IM) are recruited to the TME by neoplastic cells, where they become immunosuppressive tumor associated macrophages (TAM). Here we report that mCRC expression of the chemokine CCL2 facilitates recruitment of CCR2(+) IM from the bone marrow to the peripheral blood. Immune monitoring of circulating monocytes in patients with mCRC found this influx was a prognostic biomarker and correlated with worse clinical outcomes. At the metastatic site, mCRC liver tumors were heavily infiltrated by TAM, which displayed a robust ability to dampen endogenous anti-tumor lymphocyte activity. Using a murine model of mCRC that recapitulates these findings from human disease, we show that targeting CCR2 reduces TAM accumulation in liver metastasis and restores anti-tumor immunity. Additional quantitative analysis of hepatic metastatic tumor burden and treatment efficacy found that administration of a small molecule CCR2 inhibitor (CCR2i) improves chemotherapeutic responses and increases overall survival in mice with mCRC liver tumors. Our study suggests that targeting the CCL2/CCR2 chemokine axis decreases TAM at the metastatic site, disrupting the immunosuppressive TME and rendering mCRC susceptible to anti-tumor T-cell responses.
Author Info: (1) Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA. (2) Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA. (3
Author Info: (1) Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA. (2) Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA. (3) Department of Surgery, University of Rochester Medical Center, Rochester, NY, USA. Tumor Immunology Program, University of Rochester Medical Center, Rochester, NY, USA. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA. (4) Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA. (5) Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA. (6) Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. Alvin J Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. (7) Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA. Alvin J Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. (8) Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA. Alvin J Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. (9) Department of Surgery, University of Rochester Medical Center, Rochester, NY, USA. Tumor Immunology Program, University of Rochester Medical Center, Rochester, NY, USA. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA. (10) Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA. Alvin J Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.
