IGFBP2 promotes immunosuppression by regulating macrophage PD-L1 expression in NEUROD1-high small cell lung cancer

BACKGROUND: The 5-year survival rate for small cell lung cancer (SCLC) remains low. Immune tolerance is a significant characteristic of this disease and plays a crucial role in its malignant progression. Insulin-like Growth Factor Binding Protein 2 (IGFBP2) has attracted widespread attention as a potential therapeutic target in cancer, but its role in SCLC remains to be elucidated. METHODS: This study investigated the association between IGFBP2 secreted by NEUROD1-high small cell lung cancer (SCLC-N) and the expression of programmed cell death ligand 1 (PD-L1) in tumor associated macrophages (TAMs) using multiplex immunohistochemistry (mIHC), western blotting (WB), quantitative PCR (qPCR) and immunofluorescence (IF) following co-culture TAMs with SCLC cells. The infiltration and exhaustion of CD8 + T lymphocytes were detected using qPCR, mIHC, flow cytometry and ELISA. Subcutaneous syngeneic model using Lewis lung carcinoma (LLC) cells employed to elucidate the functions of IGFBP2. The upstream regulation mode of IGFBP2 high expression in SCLC-N was explored through integrated analysis of ChIP-seq and CUT&Tag data. Furthermore, the mechanism by which IGFBP2 promotes PD-L1 expression in TAMs was defined by constructing wild-type (WT) and NLSmutant (MUT) IGFBP2 overexpression plasmids. RESULTS: This study reveals that IGFBP2 is upregulated in SCLC-N cell lines and tissues. Furthermore, high IGFBP2 expression in SCLC-N promotes the shift of TAMs toward M2-type TAMs (M2-TAMs) and induces PD-L1 expression. This IGFBP2-induced PD-L1 elevation in TAMs correlates with reduced CD8 + T cell infiltration and enhanced T-cell exhaustion. Functionally, in vivo administration of recombinant IGFBP2 promotes tumor growth and attenuates the efficacy of PD-L1 inhibitors. Mechanistically, NEUROD1 directly binds to the IGFBP2 promoter and activates its expression in SCLC-N. Moreover, nuclear translocation of IGFBP2 is required for promoting PD-L1 expression in TAMs. CONCLUSIONS: Our research supports the idea that IGFBP2 secreted by SCLC-N cells stimulates immunosuppression via promoting the PD-L1 expression in TAMs.