Novel potential predictive biomarker to immunotherapy (Io) treatment in metastatic colorectal cancer (mCRC) patients: The role of the VHIO immune gene-expression signature (VIGex)

Although the clinical development of Io has ushered in a new era of anti-tumor therapy, mCRC is considered to be an immune-excluded tumor, being one of the tumor types in which Io has proven to be less effective. Microsatellite instability (MSI) status is currently the only biomarker for Io response in mCRC, being present in only 5% of mCRC pts. Most pts with microsatellite stability (MSS) mCRC do not respond to Io or do not have durable clinical responses, therefore it is necessary to obtain reliable predictors of response to Io. Here we report a novel potential biomarker based on RNA expression data. The VIGex test is a gene expression panel using RNA data, developed from a set of 12 immune-related genes (interferon-γ signaling, T-cell exhaustion, Tregs, tumor-associated macrophages, and anti-inflammatory cytokines). Gene expression analysis was performed using Nanostring nCounter and analyzed with nSolver software and R in-house scripts. After intra- and inter-run normalization, an unsupervised hierarchical clustering with Ward’s minimum variance method and correlation-based distance was performed. 3 clusters (hot, intermediate (iCold), and cold) were defined by an unsupervised hierarchical clustering of the VIGex results. Overall, 383 pts with VIGex test and mCRC were detected. 254 (66%) tissue samples were obtained from the metastatic site and 129 (34%) from the primary site. 105 pts were classified as hot (28%), 223 as iCold (58%), and 55 as Cold (14%). A correlation between immune-related gene expression and cluster score VIGex classification was seen, as the cluster of cold VIGex tumors showed low expression of immune-related genes, and the Hot VIGex tumor cluster was associated with high expression of immune-related genes. Our results shows that the VIGex score reflects the immune microenvironment status of mCRC, being a potential predictive biomarker to Io to explore in this subset of pts. This feasible test could be an enrichment strategy to improve selection of MSS mCRC pts exploring the use of Io in clinical trials.