High-risk gene expression in colorectal liver metastasis: Potential for novel therapies.

Abstract

147 Background: Over half of patients with colorectal cancer (CRC) develop liver metastases. While immunotherapy is an emerging treatment of solid tumors, its use among CRC patients is limited. Furthermore, gene expression patterns of liver-specific CRC metastases remain unclear. The purpose of this study was to identify a high-risk gene expression profile for patients with colorectal liver metastasis (CRLM) to better inform prognosis and development of novel targeted therapies. Methods: Fifty-three FFPE CRLM samples from patients who underwent complete metastatectomy from 2009-2017 were examined. Expression profiling of extracted RNA was performed using NanoString Immuno-Oncology (IO360) 750-gene panel. Statistical analyses using cutoffs of absolute log 2-fold change≥1.5 and p-value≤0.05 were performed. Patients were analyzed by extremes of outcomes: survival time in the lowest quartile compared to those still alive at last follow-up. Results: Eight differentially expressed genes were associated with poor survival. Overexpressed genes included IL6R, CXCL2, C7, MGMT, PCK2, CSF1 and LILRB4 (Table). PLA2G2A was under-expressed. Conclusions: This study demonstrates differential gene expression associated with poor survival among patients with CRLM. Specific genes of interest include IL6R, MGMT, CSF1 and LILRB4. IL6R is a known effector in tumor proliferation via IL-6 signaling from tumor-associated macrophages, myeloid-derived suppressor cells (MDSCs) and T-cells. MGMT repairs alkylating DNA damage and is implicated in carcinogenesis and response to chemotherapy. CSF1 promotes macrophage differentiation to M2 phenotype, suppressing inflammation and anti-tumor defense mechanisms. LILRB4 activation via MDSCs leads to T-cell inhibition. These overall suggest a myeloid-dominant tumor immune microenvironment and represent important potential therapeutic targets. Next steps include performing immunohistochemistry to validate findings at the protein level and investigate the tumor intrinsic role using human cell lines.[Table: see text]