Pan-cancer and single-cell analyses identify CD44 as an immunotherapy response predictor and regulating macrophage polarization and tumor progression in colorectal cancer.

ABSTRACT

Introduction: Cluster of differentiation (CD) 44 is a non-kinase cell surface transmembrane glycoprotein critical for tumor maintenance and progression. Methods: We conducted a systematic analysis of the expression profile and genomic alteration profile of CD44 in 33 types of cancer. The immune characteristics of CD44 were comprehensively explored by TIMER2.0 and CIBERSORT. In addition, the CD44 transcriptional landscape was examined at the single-cell level. Then, Pseudotime trajectory analysis of CD44 gene expression was performed using Monocle 2, and CellChat was utilized to compare the crosstalk differences between CD44+monocytes and CD44- monocytes. Tumor immune dysfunction and exclusion (TIDE) was used to evaluate the predictive ability of CD44 for immune checkpoint blockade (ICB) responses. The effects of CD44 on colorectal cancer (CRC) and macrophage polarization were investigated by knocking down the expression of CD44 in HCT-116 cell and macrophages in vitro. Results: The expression of CD44 elevated in most cancers, predicting unfavorable prognosis. In addditon, CD44 was correlation with immune cell infiltration and key immune regulators. CD44+ monocytes had a higher information flow intensity than CD44- monocytes. CD44 had good predictive ability for immune checkpoint blockade responses. Knockdown of CD44 inhibited the proliferation, migration, and invasion of HCT-116 cell in vitro. Knockdown of CD44 inhibited M2 macrophage polarization. Discussion: These findings suggest that CD44 is involved in regulating tumor development, macrophage polarization, and has certain predictive value for patient clinical prognosis and response to immunotherapy.