Data Sheet 1_Multimodal characterization of HLA-G expression across solid tumors reveals transcript-protein discordance and implications for immunotherapy targeting.pdf

Introduction<p>Human leukocyte antigen-G (HLA-G) is a non-classical major histocompatibility complex class I molecule that functions as an immune checkpoint via inhibitory receptors such as immunoglobulin-like transcript 2 (ILT2), immunoglobulin-like transcript 4 (ILT4) and killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4), suppressing anti-tumor immunity. Its prevalence and regulation across solid tumors remain incompletely defined due to low expression, spatial heterogeneity, and detection challenges.</p>Methods<p>We performed a multimodal target prevalence analysis integrating data from a validated immunohistochemistry (IHC) assay for protein detection and prospective screening data from a phase 1 study of an HLA-G × CD3 T cell bispecific antibody (Clintrials.gov identifier: NCT05769959) with bulk RNA sequencing from early-phase oncology clinical trials.</p>Results<p>Analysis of 252 patient tumor samples using an investigational HLA-G IHC assay showed that 59.9% were HLA-G positive, with highest prevalence in ovarian cancer (89%), non-small cell lung cancer (NSCLC) (76%), renal cell carcinoma (RCC) (71%), and pancreatic cancer (70%).

Expression was generally low to moderate and spatially heterogeneous. Notably, discordance between transcript and protein expression was observed in melanoma, where high mRNA levels were not matched by detectable protein, suggesting post-transcriptional regulation. Prospective screening in a phase 1 cohort confirmed a high target positivity rate (77.5%).