Myeloid Response Score (MRS): A Simple Signature That Reveals the Myeloid Contexture and Predicts the Prognosis of Hepatocellular Carcinoma

Abstract

Abstract Myeloid cells, including monocytes/macrophages (Mo/Mϕ), neutrophils, and dendritic cells, can mediate divergent immune responses according to different pathological conditions. In cancer, myeloid cells play important roles in disease progression and therapy, suggesting that appraising the overall and exact intratumoral myeloid response may provide valuable information that may help to predict cancer prognosis and tailor more precise therapies. In this study, we screened biomarkers that cover major myeloid subtypes in human tumors, then constructed and validated a simple prognostic signature, called Myeloid Response Score (MRS), based on a dataset from a multi-center cohort of 1,177 HCC patients. Using multiplex immunofluorescence staining, we observed a shift of predominant myeloid population from CD169+, CD169−CD11b−CD14+, and CD169−CD11b−CD163+ Mo/Mϕs in MRSlow HCC to neutrophils and CD11b+CD169− Mo/Mϕs in MRShigh tumor. Transcriptomic and flow cytometric analyses showed that MRShigh HCC exhibited patterns of CD8+ T cell exhaustion including impaired cytotoxicity and increased PD-1 expression, suggesting highly suppressive immune microenvironment. The “climb trajectory” of MRSs between HCC tumors were depicted using the TCGA dataset, and was linked to CD8+ T cell dysfunction and poorer survival of patients. Moreover, MRS-based nomograms were highly discriminative, accurate, and useful in predicting HCC prognosis and we provide additional evidence that MRS may associate with the efficacies of post-recurrence sorafenib and transcatheter arterial chemoembolization (TACE) treatments. Together, we constructed and validated a new myeloid signature with valuable immunological and clinical potential.