Abstract 3385: Cancerous tissue can be identified by the presence of oxMIF, the oxidized form of macrophage migration inhibitory factor

Abstract

Abstract Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine and is pathologically associated with several types of cancer. We identified oxMIF, an immunological and conformationally distinct isoform of MIF that can be mimicked in vitro by mild oxidation of recombinant MIF. Fully human monoclonal antibodies that specifically target oxMIF were shown to inhibit signaling pathways associated with tumor proliferation and progression in vitro and in vivo in syngeneic or xenogeneic animal models. To evaluate the use of oxMIF as a biomarker of malignant tissue, we acquired plasma and tumor tissues from patients with colorectal cancer (CRC), ovarian, and non-small cell lung cancer (NSCLC), as well as control plasma and control tissue from healthy donors, i.e. in a normal state of health, with no apparent signs of disease. We developed a novel immunohistochemistry (IHC) method to detect oxMIF in malignant tissues and used a specific new ELISA to detect oxMIF in plasma. In patients with CRC, we detected oxMIF by IHC in primary tumors (31 of 39) and in liver, lung and lymph-node metastases (n = 10). Staining intensities showed variation between different tumor cells, as well as in the microenvironment. Similarly, we detected oxMIF by IHC in most types of ovarian cancer (n = 42), but not in controls (n = 4), and observed some variations in the localization and intensities of staining. We also detected oxMIF in liver metastases from patients with ovarian cancer (n = 2). In patients with NSCLC (n = 32), 22 samples showed a strong staining for oxMIF. In tissues from healthy donors (4 colon, 4 ovary and 3 lung), oxMIF was not or barely detectable, whereas total MIF (sum of reduced and oxidized MIF) was widely expressed in normal and tumor tissues and showed a more diffuse spatial distribution than oxMIF. In commercially acquired plasma samples from patients with CRC (n = 46) and NSCLC (n = 15), we did not observe a significant increase of oxMIF levels (median = 0 for both) compared with the plasma from healthy donors (median = 0; n = 69). In patients with ovarian cancer, significant increased levels of oxMIF were measured in plasma (median = 3.5ng/mL, n = 42), and more specifically from patients with papillary serous cystadenocarcinoma or serous cystadenocarcinoma compared with clear cell adenocarcinoma (medians = 3.5, 4.0, and 0 ng/mL respectively). Our studies demonstrated that oxMIF is a disease-related isoform of MIF that can be specifically detected in tissues from various types of cancer. We therefore suggest that oxMIF reflects a new biomarker in solid tumors and has potential diagnostic and prognostic value. A phase 1 clinical study of a novel human antibody that selectively targets oxMIF is currently ongoing in patients with solid malignancies (ClinicalTrials.gov identifier: NCT01765790). Citation Format: Nicolas Sabarth, Dirk Völkel, Michael Thiele, Alexander Schinagl, Patrice Douillard, Friedrich Scheiflinger, Randolf Kerschbaumer. Cancerous tissue can be identified by the presence of oxMIF, the oxidized form of macrophage migration inhibitory factor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3385. doi:10.1158/1538-7445.AM2015-3385