Synergistic camrelizumab therapy inhibits P53-mutant osimertinib-resistant solid lung adenocarcinoma via the TGF-β signaling pathway.

BACKGROUND: Lung adenocarcinomas (LACs) are classified into several histological types. The clinical outcomes are not consistent in epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistant LACs treated by immune checkpoint inhibitors (ICIs). This study aims to explore the regulatory mechanisms of EGFR-mutant LAC and programmed cell death ligand 1 (PD-L1) protein expression in the tumor microenvironment (TME), as well as the pathological responses and related mechanisms of these pathways in osimertinib-resistant patients after ICI treatment. The effects of transforming growth factor-β (TGF-β) signaling pathway which remodels TME should be investigated. METHODS: Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyse differentially expressed genes (DEGs) from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) (GSE68465) cohorts. Expression of PD-L1 and cytokines were analyzed by immunohistochemistry and cytometric bead array. Osimertinib-resistant solid LAC xenografts were implanted into immune-humanized mice to demonstrate pathological responses after EGFR-TKI and ICI. TGF-β signaling proteins, pERK1/2, pSTAT3, and PD-L1 was detected by western blotting. Clinical responses were observed in 12 osimertinib-resistant patients treated by ICI. RESULTS: GO and KEGG analyses highlighted "cytokine-cytokine receptor interaction" and "TGF-beta signaling pathway". Heterogeneous PD-L1 expression was regulated by synergistic IL-6/STAT3, TGF-β and EGFR pathways. Significant tumor remission and inhibition of TGF-β signaling pathway were found in EGFR-TKI plus ICI treatment in mice models. Osimertinib-resistant solid LACs treated by ICI had better clinical outcomes. CONCLUSIONS: TGF-β signaling pathway is associated with PD-L1 expression and the pathological remission treated by EGFR-TKI and ICI. Solid osimertinib-resistant LACs by ICI can be beneficial through the inhibition of TGF-β signaling pathway.