Abstract 3021: CCR5 inhibition: macrophage repolarization therapy for colorectal cancer

Abstract

In patients with metastatic colorectal cancer (CRC), the local immune response influences the clinical course. An in-depth analysis of the invasive margin of human CRC liver metastases revealed a distinct immunological microenvironment. Within this microenvironment, two distinct subsets of myeloid cells induce an influx of T cells into the invasive margin via CXCL9/CXCL10. CCL5 is produced by these T cells and stimulates pro-tumoral effects via CCR5, creating an exploitive loop. CCR5 was found on macrophages, lymphocytes and on the vast majority of tumor cells. Inhibition of CCR5 in patient-derived functional in vitro organotypic culture models showed a promising macrophage repolarization with anti-tumoral effects. These effects are mediated by activation of an antiviral program in macrophages, leading to interferon and reactive oxygen species production and subsequent selective tumor cell death. These anti-tumoral effects were confirmed in a phase I trial with a CCR5 antagonist in 14 patients with liver metastases of advanced refractory CRC. Treatment with the oral CCR5 Inhibitor was very well tolerated and objective responses were seen, especially in combination with previously ineffective chemotherapy. Biopsies revealed mitigation of tumor-promoting inflammation within the tumor tissue, confirming the validity of the explant model and highlighting the feasbility of this approach. It furthermore shows the proof-of-concept for macrophage repolarization in cancer patients. Citation Format: Niels Halama, Inka Zoernig, Anna Berthel, Christoph Kahlert, Fee Klupp, Meggy Suarez-Carmona, Karsten Brand, Juergen Krauss, Felix Lasitschka, Alexis Ulrich, Juergen Weitz, Martin Schneider, Markus Buechler, Laurence Zitvogel, Thomas Herrmann, Axel Benner, Christina Kunz, Stephan Luecke, Christoph Springfeld, Christine S. Falk, Dirk Jaeger. CCR5 inhibition: macrophage repolarization therapy for colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3021. doi:10.1158/1538-7445.AM2017-3021

Interfering with CCL5/CCR5 at the Tumor-Stroma Interface

“…Myeloid cells unleashed from the inhibitory activity of CCL5 activated STAT3 and reduced the production of VEGF, MIF, and IL-1RA while enhancing the release of IFN-g, IFN-a2, and reactive nitrogen species (RNS); these factors contributed to tumor killing, as well as reshaping macrophage compartment by reducing CD163 + cells (Figure 1). The myeloid phenotypic switch was confirmed in biopsies from patients in response to CCR5 interference therapy (Halama et al, 2016).…”

“…In this issue of Cancer Cell, Halama et al (2016) further advance chemokine interference as a therapeutic option for cancer by demonstrating the effect of CCR5 blockade in reshaping macrophage polarization toward an anti-tumor functional state in patient-derived tumor models and liver metastases of colorectal cancer patients.…”

“…The microenvironment of liver CRC metastases is deeply conditioned by a chemokine and chemokine receptor axis involving CCL5 and CCR5, respectively. In this issue of Cancer Cell, Halama and colleagues report the consequences of restraining this loop by inhibiting CCR5 in a fully human ex vivo CRC metastasis explant model, as well as in a pilot clinical study in patients with advanced CRC (Halama et al, 2016). Authors demonstrate that within the CRC invasive margins, T cells, attracted by CXCL9 and CXCL10 released by CD68 + and CD11b + myeloid elements, stimulate the tumor growth and invasiveness and promote pro-tumoral macrophage polarization by releasing CCL5 (Figure 1).…”

“…Moreover, the T lymphocytes producing CCL5 in liver metastasis are considered to be exhausted because they express PD-1 and are surrounded by macrophages that express PD-L1. However, while release of IFN-g by T lymphocytes (CD8 + T cell in particular) is one of the main mechanisms supporting the tumor environmental upregulation of PD-L1 (Page et al, 2014;Palucka and Coussens, 2016), livermetastasis-infiltrating T cells produce CCL5 but no IFN-g (Halama et al, 2016), suggesting an additional, unidentified regulatory circuit. CCL5/CCR3 signaling promotes metastasis formation in luminal breast cancer via Th2 polarization of CD4 + T cells, which have been implicated in fueling chronic inflammation by skewing myeloid cells toward a pro-tumoral and tolerogenic function (Palucka and Coussens, 2016;Velasco-Velá zquez et al, 2014).…”

“…Targeting chemokines in combination with chemotherapy may be beneficial, given that cytotoxic agents can increase the immunogenicity by killing tumor cells and by restraining immunosuppressive lymphoid and myeloid populations (Palucka and Coussens, 2016). This might be the case for CCL5/CCR5 interference as well (Figure 1), because objective partial responses were reported in three out of five patients who received a combination of maraviroc and chemotherapy (Ugel et al, 2015;Halama et al, 2016). It should be noted that the selected pa-tients' population included heavily pretreated CRC subjects, and the chance of response in this setting is typically less than 10%.…”