Heterogeneity In The Immune Inflamed Biomarkers Of Mss And Msi Colorectal Cancer

MSI status in metastatic colorectal cancer (mCRC) is associated with benefit from immune checkpoint inhibitors (ICI). However, this biomarker needs to be refined towards a better patient selection. Other biomarkers besides MSI have been explored, including high PD-L1 expression in tumor cells or tumor infiltrating immune cells, high prevalence of tumor-infiltrating lymphocytes and B cells, IFN-g signatures and high tumor mutational burden. Here we explore the immune cell landscape and inflamed biomarkers in MSS and MSI primary colorectal tumors and metastatic lesions. We downloaded The Cancer Genome Atlas colorectal RNA-seq data (RPKM) and MSI status from cBioportal (Cerami et al 2012). The abundance of 64 distinct immune or stromal cell types was inferred through xCell (Aran et al 2017). xCell outperforms methods to portrait tumoral cell infiltration by learning from the expression profiles of thousands of pure cell types and validating the signatures through in-silico simulations and flow cytometry phenotyping. IFN-g signature (6 genes) was calculated as specified in Ayers et al 2017. MSI colorectal tumors tended to present high expression of PD-L1, an IFN-g signature and CD8+ Tcell infiltration, in contrast to MSS cases (p < 0.001). However, CD8+Tcell infiltration and high levels of IFN-g signature were not constant in MSI tumors, while some MSS tumors presented an IFN-g signature and high PD-L1 expression. Interestingly, some MSI tumors showed high presence of myeloid cells (p < 0.001) and B cells were present in the tumors presenting high levels of CD8 T cell infiltration but also in some MSS tumors with low CD8 T cell infiltration. An important group of MSS tumors showed high infiltration on NK cells (p < 0.001). Presence of endothelial cells was independent of microsatellite status, although there was an increased presence of fibroblasts in the MSS tumors (p = 0.012). MSI status is not an optimal biomarker to classify inflamed mCRC. These tumors present a complex inmune-biology which includes multiple immune-phenotypes that could be responsible for the diversity on immune-responses in MSI and MSS mCRC. The implementation of multiomic approach is necessary to improve clinical efficacy of cancer inmunotherapy in mCRC.