Macrophage Susceptibility to Emactuzumab (RG7155) Treatment

Abstract

Blockade of colony-stimulating factor-1 receptor (CSF-1R) enables the therapeutic targeting of tumor-associated macrophages (TAM) in cancer patients. Various CSF-1R inhibitors, mAbs, and tyrosine kinase inhibitors are currently evaluated in early clinical trials. Presence of an alternative survival signal, such as GM-CSF, rescues human monocyte-derived macrophages from CSF-1R inhibitor-induced apoptosis. In this study, we sought to identify additional factors that mediate resistance to CSF-1R-blocking antibody RG7155 (emactuzumab). We investigated the impact of hypoxia, macrophage-polarizing cytokines IL4 and IL10, and genetic alterations within the CSF1R locus and mitochondrial DNA. Among all investigated factors, only IL4 completely rescued viability of RG7155-treated macrophages in vitro This RG7155-resistant population was characterized by a substantially increased mannose receptor-1 (CD206) expression. Analysis of CD206 and the hemoglobin scavenger receptor CD163 expression on normal tissue allowed for discrimination of distinct macrophage populations according to localization and frequency. In emactuzumab-treated cancer patients, we found a significant reduction of CSF-1R, CD204, and CD163 mRNA levels in contrast to a less pronounced decrease of CD206 expression by transcriptome analysis of tumor biopsies. However, we detected in normal skin tissue, which shows lower IL4 mRNA expression compared with melanoma tissue, significant reduction of CD206 dermal macrophages in RG7155-treated skin biopsies. These results suggest that in cancers where the cytokines IL4 and GM-CSF are sufficiently expressed to induce very high CD206 expression on macrophages, CSF-1R inhibition may not deplete CD206 TAM. This observation can help to identify those patients most likely to benefit from CSF-1R-targeting agents. Mol Cancer Ther; 15(12); 3077-86. ©2016 AACR.

Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy

“…For both strategies, the choice of an appropriate combination partner will be key to reprogramming a tumor-promoting TME or boosting a pre-existing anti-tumor immune response. Recently, in vitro-differentiated CD206-expressing human macrophages were shown to be rescued from emactuzumab-induced depletion in the presence of IL-4 [50], demonstrating the importance of the local cytokine micromilieu. As CD206 expression is high on alveolar macrophages, an elevated concentration of IL-4 in lung cancer patients may result in resistance to CSF1R inhibitors.…”

Progress in tumor-associated macrophage (TAM)-targeted therapeutics

“…Documenting patients’ genetic profile and the corresponding therapeutic outcome are also beneficial in correlation studies to better predict patient response as well as in refining drug development. In the case of CSF-1R inhibition therapy, certain single nucleotide polymorphisms (SNPs) in CSF-1R have been identified that reduce the potency of emactuzumab [226]. Nonetheless, the study may help in the future design of the next-generation CSF-1R blockade therapy.…”

Reprogramming of Tumor-Associated Macrophages with Anticancer Therapies: Radiotherapy versus Chemo- and Immunotherapies

“…CSF1-deficient mice showed a 50% decrease in macrophage infiltration while neutrophil infiltration was increased during tumor progression in a mouse model of pancreatic islet cancer (55). mAbs and small molecules targeting CSF1 (mAb anti-CSF1) or CSF1-R (BLZ945, emactuzumab, PLX3397) were subjected to numerous studies and were shown to deplete macrophages in a tissue-specific manner (56, 57). Overall, CSF1-R inhibitors deplete TAMs and abolish tumor growth, angiogenesis, and metastasis.…”