Abstract 5868: Differential tumor immunity in limited-stage vs extensive-stage small cell lung cancer
Authors: Jiyeon Kim, Jun-Gi Jeong, Sehhoon Park, Hyun Ae Jung, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Se-Hoon Lee
Journal: Cancer Research (2025)

Abstract Introduction: Small cell lung cancer (SCLC) is an aggressive malignancy characterized by rapid progression and early metastasis. Immunotherapy has become the standard treatment for extensive-stage SCLC (ES-SCLC), but its role in limited-stage SCLC (LS-SCLC) remains under investigation in clinical trials. This study aims to explore the differences in tumor immune microenvironment (TIME) of LS-SCLC and ES-SCLC and to suggest how these differences may influence therapeutic strategies and patient outcomes. Methods: Samples from 365 patients were collected with histologically confirmed SCLC who had available tissue samples. Whole transcriptome sequencing (WTS) was performed on all samples. The patients were categorized based on clinical staging at the time of biopsy. Using WTS data, immune cell composition was analyzed using CIBERSORTx deconvolution algorithm, and the signature was calculated as the mean of the Transcripts Per Million (TPM) values using curated genes. edgeR was used for differential gene expression and performed GSEA using KEGG pathway database. SCLC subtypes were assigned based on lineage-defining transcription factor (TF) markers (as described by S Park, et al., eBioMedicine, 2024). Statistical significance was evaluated when the P value was below 0.05. Results: Of the 365 patients, 100 were classified as LS-SCLC, and 265 as ES-SCLC. The median age was 65.3 years for LS-SCLC and 67.8 years for ES-SCLC. The LS-SCLC included 6% never smokers, while the ES-SCLC cohort comprised 8.3% never smokers. Biopsy site distribution was as follows: in LS-SCLC, 28% of tissues were obtained from the lung, bronchus, or trachea, 72% from lymph nodes. Similarly in ES-SCLC, 23% of tissues were from the lung, 69% from lymph nodes, and 9% from other distant organs. Immune cell profiling identified stage-specific differences in the immune landscape. LS-SCLC exhibited significantly higher levels of B cells and activated dendritic cells (DCs), whereas ES-SCLC showed increased proportions of resting DCs and neutrophils. The angiogenesis signature was significantly elevated in ES-SCLC, reflecting distinct immune-modulating effects in TIME. Differential gene expression revealed enrichment of KEGG gene sets related to the peroxisome proliferator-activated receptor (PPAR) signaling and ERBB signaling in ES-SCLC. Subtype distribution based on WTS data showed a significant difference between stages, with the ASCL1 subtype (SCLC-A) more frequent in LS-SCLC and the POU2F3 subtype (SCLC-P) more common in ES-SCLC. Conclusions: Our findings highlight significant differences in the TIME and molecular subtypes between LS-SCLC and ES-SCLC. These differences may inform the development of tailored therapeutic strategies, ultimately improving patient outcomes by addressing the unique immune and molecular characteristics of LS-SCLC and ES-SCLC. Citation Format: Jiyeon Kim, Jun-Gi Jeong, Sehhoon Park, Hyun Ae Jung, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Se-Hoon Lee. Differential tumor immunity in limited-stage vs extensive-stage small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5868.