LRP1B affects lung adenocarcinoma immunotherapy efficacy via ferroptosis

Abstract Background Currently, the clinically used immune biomarkers for non-small cell lung cancer (NSCLC) are programmed death ligand 1 (PD-L1) and tumor mutation burden (TMB). However, they cannot accurately predict the effectiveness of immunotherapy. Identifying appropriate biomarkers that can differentiate between beneficiary groups is imperative. Methods We identified LRP1B as a potential biomarker for immunotherapy by analyzing clinical data, combined with bioinformatics analysis. The effects of LRP1B on ferroptosis were assessed using qRT-PCR, Western blotting, CCK-8 assay, and flow cytometry. The potential mechanism underlying the regulation of ferroptosis by LRP1B was elucidated using qRT-PCR, Western blotting, ChIP, and dual-luciferase reporter gene assays. Results Through the collection and analysis of clinical data, we had established that LRP1B mutation is a highly promising biomarker for immunotherapy. Bioinformatics analysis revealed significant differences in the expression levels of PD-L1 and TMB between patients with LRP1B mutation and wild-type patients in lung adenocarcinoma (LUAD), while in lung squamous cell carcinoma (LUSC), only the level of TMB showed a significant difference. Furthermore, we observed that patients with LRP1B mutation in LUAD had significantly higher levels of tumor-infiltrating lymphocytes (TILs), including CD4 + T cells and M1 macrophages, than wild-type patients, whereas in LUSC, no such differences were detected. In addition, we found that patients with LRP1B mutation in LUAD had significantly prolonged progression-free survival (PFS) compared to wild-type patients, but no PFS benefit was observed in patients with LRP1B mutation in LUSC. These findings provided strong evidence that LRP1B mutation was a potential biomarker for immunotherapy in LUAD. Moreover, our in vivo experiments indicated that knockdown of LRP1B enhanced the efficacy of mPD-1, and mechanistic studies revealed that LRP1B regulated the sensitivity of cells to ferroptosis by modulating the expression of SLC7A11 through altering the phosphorylation level of STAT3. Importantly, LRP1B alterations also affected the sensitivity of cells to ferroptosis induced by IFN-γ. Further analysis revealed that LRP1B knockdown promoted immunotherapy in vivo. Conclusions Our results confirmed that LRP1B affected the efficacy of immunotherapy by modulating the sensitivity of NSCLC cells to ferroptosis.