Abstract 320P
Background
Small cell lung cancer (SCLC) is a highly metastatic neuroendocrine cancer with high lethality. It exhibits intratumor heterogeneity and genomic instability. Previous studies have shown radiotherapy (RT) plus immune checkpoint inhibitors (ICIs) has a synergistic anti-tumor effect in SCLC, but tumor relapse still occurs. Therefore, it’s essential to elucidate the mechanism of relapse to combined therapy and explore the new therapeutic targets in SCLC.
Methods
We established a murine SCLC model and used multi-omics methods to investigate the dynamic changes of SCLC from treatment sensitivity to relapse following radioimmunotherapy, particularly focusing on the role and mechanisms of lysine-specific demethylase 1 (LSD1) during the relapse. Additionally, we evaluated the anti-tumor efficacy of the triple therapy of RT + ICI + LSD1 inhibitor (SP2509) in SCLC.
Results
Dynamic single-cell RNA-Seq data revealed that LSD1 expression was elevated in relapsed SCLC tumor cells, suggesting that these cells may exhibit lower sensitivity to RT + ICI treatment and contribute to tumor relapse following radioimmunotherapy. Then we used CRISPR technology to delete LSD1 in murine SCLC cells. LSD1-targeted sgRNA transduction successfully reduced LSD1 protein levels and downregulation NeuroD1 expression. When these cells were subcutaneously inoculated into C57BL/6J mice, CRISPR-mediated LSD1 knockout demonstrated an enhanced response to radioimmunotherapy and prolonged the mouse survival. Similarly, treatment with LSD1 inhibitor SP2509 produced comparable results, with the complete response rate of tumors increasing threefold to 60% under the triple therapy regimen of RT + ICI + SP2509. Flow cytometry analysis further revealed that LSD1 inhibition or knockout led to increased MHC-I expression and significantly enhanced T-cell infiltration within the tumor microenvironment.
Conclusions
In our murine SCLC model, Lsd1+ tumor cells were found to be associated with relapse following RT + ICI treatment. Inhibition or knockout of LSD1 suppressed NeuroD1 and neuroendocrine transcriptional programs, increased T-cell infiltration, and delayed tumor relapse to radioimmunotherapy.
Legal entity responsible for the study
F. Na.
Funding
This research was funded by West China Hospital (no. ZYJC21003), the Natural Science Foundation of Sichuan Province (no. 2024NSFSC1908 and 2025NSFSC1997), and the National Natural Science Foundation of China (no. 82472783).
Disclosure
All authors have declared no conflicts of interest.