LTBR acts as a novel immune checkpoint of tumor-associated macrophages for lung adenocarcinoma immunotherapy

Description

Background: Tumor-associated macrophages (TAMs) has been reported to mediate the resistance of LUAD patients to ICI therapy. However, its underlying mechanisms and whether TAMs could be promising targets to overcome the non-response after ICI application remain to be unveiled. Methods: Immune multi-omics analysis was implemented with a large clinical cohort encompassing 1045 LUAD cases to screen out potential immune checkpoints. scRNA-seq analysis revealed their distribution in LUAD immune cells. The key molecule and related mechanisms were investigated in vitro and in vivo. Clinical verification in ICI therapy cohorts and TAMs-targeted delivery system had been performed for further clinical translation. Findings: LTBR, as a potential immune checkpoint, was screened out. Its high expression, duplication and low methylation were corelated with LUAD unfavorable survival. scRNA-seq and FACS analysis showed the highest expression of LTBR in TAMs. Moreover, TAM-targeted inhibition of LTΒR disrupted TISM following with CD8+ T cell boost as well as G-MDSC and M2-like TAM reduction, especially improved the therapeutic effect of ICI. Further studies showed that LTΒR maintained TAM immunosuppressive activity and M2 phenotype by non-canonical NF-kB signaling and Wnt/beta-catenin signaling. Clinical investigation indicated that LTΒR could predict LUAD stages, immunotherapy responses and clinical outcomes after ICI treatment. Conclusions: Through integrative analysis of immune Multi-Omics and ScRNA-seq data (iMOS), our study develops an immune-checkpoint discovery pipeline, and identifies LTBR as a novel immune checkpoint of TAMs that orchestrates TISM through non-canonical NF-kB and Wnt/beta-catenin signaling. Finally, we propose a promising strategy by targeting LTBR+ TAMs for improving the effect of ICI therapy.

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