FOLR2+ macrophage depletion from intestinal metaplasia to early gastric cancer: single-cell sequencing insight into gastric cancer progression.

Abstract

Background: The immune landscape associated with different subtypes of intestinal metaplasia (IM) and early gastric cancer (EGC) remains unclear. This study aimed to investigate the immune landscape of complete intestinal metaplasia (CIM), incomplete intestinal metaplasia (IIM), and EGC, as well as the underlying mechanisms of EGC progression.

Methods: Gastric biopsy samples were collected from five patients with CIM, six patients with IIM, and four patients with EGC, followed by single-cell RNA sequencing. Multiplex immunohistochemical staining was employed to validate the samples from the aforementioned patients. To elucidate the potential mechanisms involved, in vitro coculture experiments were conducted using FOLR2⁺/FOLR2^- macrophages and CD8⁺ T cells. Flow cytometry was utilized to investigate the biological functions of FOLR2⁺ macrophages in the progression of EGC.

Results: Five subpopulations of macrophages were identified in CIM, IIM and EGC samples. FOLR2⁺ macrophages possess antitumor immune potential, and the proportion of FOLR2⁺ macrophage gradually decreased from the CIM stage to the IIM and EGC stages. FOLR2⁺ macrophages were significantly positively correlated with CD8⁺ T cells and activated the cytotoxicity of CD8⁺ T cells via antigen cross-presentation. Additionally, during the progression of EGC, epithelial cells progressively upregulated APP expression, thus inducing necroptosis of FOLR2⁺ macrophages via the APP‒TNFRSF21 axis.

Conclusions: Our work provides an understanding of the potential mechanisms underlying the malignant transformation of IM mediated by FOLR2⁺ macrophages.