Abstract B037: Macrophage repolarization therapy in metastatic colorectal cancer: CCR5 inhibition

Abstract

The influence of the local immune response on the clinical course of colorectal cancer (CRC) has been analyzed extensively. Analyzing the invasive margin of human CRC liver metastases, we identified a protumoral mechanism of T-cell-derived CCL5 that leads to immune cell exploitation by tumor cells. Two distinct subsets of myeloid cells produce CXCL9/CXCL10, which induce an influx of T cells into the invasive margin. CCL5 is produced by these exhausted T cells and stimulates tumor cell proliferation and invasive behavior via CCR5 on tumor cells and macrophages. CCR5 inhibition in patient-derived functional in vitro organotypic culture models induced macrophage repolarization with anti-tumoral effects. These immunomodulatory and anti-tumoral effects of CCR5 blockade then could be confirmed in a phase I trial with a CCR5 antagonist in advanced refractory CRC patients with liver metastases. Amelioration of tumor-promoting inflammation on the tumor tissue level and objective tumor responses in advanced metastatic CRC patients were observed. Citation Format: Niels Halama, Inka Zoernig, Anna Berthel, Christoph Kahlert, Fee Klupp, Meggy Suarez-Carmona, Juergen Krauss, Karsten Brand, Felix Lasitschka, Tina Lerchl, Claudia Luckner-Minden, Alexis Ulrich, Juergen Weitz, Martin Schneider, Markus W. Buechler, Laurence Zitvogel, Thomas Herrmann, Axel Benner, Christina Kunz, Stephan Luecke, Christoph Springfeld, Christine Falk, Dirk Jaeger. Macrophage repolarization therapy in metastatic colorectal cancer: CCR5 inhibition [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B037.

Toll-Interacting Protein Regulates Immune Cell Infiltration and Promotes Colitis-Associated Cancer

“…CCR5 is an inflammatory chemokine receptor enabling recruitment of diverse immune cell types (Griffith et al, 2014). In a phase I clinical trial of metastatic colorectal cancer, drug-induced blockade of CCR5+CD4 + and CD8 + lymphocyte infiltration with maraviroc reduced interaction of lymphocytes with MFs, leading to reduced inflammation and better clinical responses (Halama et al, 2016). Ablation of chemokine receptors, such as CCR2 and CXCR2, was shown to severely abrogate leukocyte infiltration, resulting in reduced inflammation-driven colon cancer (Popivanova et al, 2008(Popivanova et al, , 2009Katoh et al, 2013).…”

Modulation of tumor‐associated macrophages in colitis‐associated colorectal cancer

“…TLR agonist R848 in combination with oxaliplatin, a treatment for colorectal cancer, can shift macrophages to the M1 phenotype, enhancing the antitumor efficacy of oxaliplatin(Liu et al, 2020). In a Phase I trial of advanced refractory colorectal cancer in metastatic liver, CCR5 blockade induced the conversion of TAMs from M2 to M1 phenotype via STAT3/SOCS3, which simultaneously reduced CD163 + cell levels and guided the remodeling of myeloid cell composition in the microenvironment(Halama et al, 2016). In addition, as bacterial flora secretes cathepsin K (CTSK) and binds to TLR4 on the surface of TAMs, activating mTOR pathway and inducing M0 to M2 phenotype polarization, Odanacatib, a specific CTSK inhibitor, is administered to inhibit related tumor-promoting effects and improve the prognosis of CRC patients (Q.…”