An AI-assisted Investigation of Tumor-Associated Macrophages and their Polarization in Colorectal Cancer

Abstract

Tumor-associated Macrophages (or TAMs) are amongst the most common cells that play a significant role in the initiation and progression of colorectal cancer (CRC). Recently, Ghosh et al.1proposed distinguishing signatures for identifying macrophage polarization states, namely, immuno-reactive and immuno-tolerant, using the concept of Boolean implications and Boolean networks. Their signature, called the Signature of Macrophage Reactivity and Tolerance (SMaRT), comprises of 338 human genes (equivalently, 298 mouse genes). However, SMaRT was constructed using datasets that were not specialized towards any particular disease. In this paper, (a) we perform a comprehensive analysis of the SMaRT signature on single-cell human and mouse colorectal cancer RNA-seq datasets; (b) we then adopt a technique akin to transfer learning to construct a “refined” SMaRT signature for investigating TAMs and their polarization in the CRC tumor microenvironment. Towards validation of our refined gene signature, we use (a) 5 pseudo-bulk RNA-seq datasets derived from single-cell human datasets; and (b) 5 large-cohort microarray datasets from humans. Furthermore, we investigate the translational potential of our refined gene signature in problems related to MSS/MSI (4 datasets) and CIMP+/CIMP-status (4 datasets). Overall, our refined gene signature and its extensive validation provide a path for its adoption in clinical practice in diagnosing colorectal cancer and associated attributes.