Effect of elevated expression of <i>LILRB4</i> and <i>TSC22D3</i> on survival in lung cancer.
Authors: Borys Hrinczenko, Tolulope Tosin Adeyelu, Wei-Zen Wei, Andrew Elliott, Gerold Bepler, Ari Vanderwalde, Balazs Halmos, Emmanuel S. Antonarakis, Maryam B. Lustberg, Jennifer Jacob
Journal: Journal of Clinical Oncology (2025)

2633 Background: HER2/neu mutations or amplifications, present in up to 23% of non-small cell lung cancers (NSCLCs), activate STAT3, promoting inflammation and suppressing adaptive immune responses. Elevated systemic inflammation-immune index (SII) in small cell lung cancer (SCLC) correlates with reduced response to PD-1/L1 immune checkpoint inhibitors (ICIs), leading to worse overall survival (OS) and progression-free survival (PFS). These findings highlight the need to mitigate inflammation in lung cancers to enhance ICI response and improve survival. Biomarker studies can identify genes that differentiate inflammatory and immune pathways, offering therapeutic insights. Methods: To identify genes regulating the HER2/neu oncogene, HER2/neu-overexpressing mice were crossed with genetically Diverse Outbred (DO) mice. The resulting DO F1 offspring were monitored for HER2/neu-expressing tumor onset and growth. Tumor phenotypes were associated with mouse haplotypes to identify quantitative trait loci (QTL) on chromosomes (chr) 2, 6, and X linked with aggressive HER2/neu tumors. Of the 35 candidate genes harboring protein-coding changes, homologous genes on human chr 1, 10, and X were analyzed using Caris Life Sciences datasets of NSCLC and SCLC: 25,143 primary NSCLC; 12,365 metastatic NSCLC; 621 primary SCLC; and 971 metastatic SCLC where primary biopsies are those taken from the lung and metastatic biopsies from sites other than the lung. Patient cohorts stratified by gene expression (top vs. bottom 50%) were correlated with OS, ICI response, and time on pembrolizumab or atezolizumab treatment (TOT). Results: Several homologous candidate genes correlated with lung cancer survival in both NSCLC and SCLC. Notably, high expression of LILRB4 , a macrophage-specific checkpoint molecule, was associated with improved survival (HR 0.66–0.84, p &lt; 0.001) across all lung cancer types and sites. Additionally, elevated TSC22D3 , a glucocorticoid receptor-activated gene regulating anti-inflammatory pathways, including LILRB4 expression, was positively associated with OS in metastatic NSCLC (HR 0.82, p &lt; 0.00001) and SCLC (HR 0.77, p &lt; 0.001). Expression of LILRB4 and TSC22D3 further enhanced survival in ICI-treated patients (SCLC: HR 0.72; NSCLC: HR 0.82; p &lt; 0.001). In NSCLC, high LILRB4 expression conferred an 18% improved TOT with pembrolizumab (HR 0.858, p &lt; 0.0001). Conclusions: LILRB4 and TSC22D3 are key genes linked to improved survival outcomes in both SCLC and NSCLC, likely through their roles in mitigating inflammation. Their association with enhanced ICI responses underscores their potential as therapeutic targets. Future research will evaluate the relationship between LILRB4 and TSC22D3 expression and HER2/neu status in NSCLC and validate protein-level correlations in positive cells. Our long-term goal is to determine the therapeutic potential of LILRB4 and TSC22D3 in SCLC, NSCLC and HER2/neu-positive NSCLC.