Serum laminin γ2 monomer (LG2m) to reflect a CD90-driven immunosuppressive niche and survival benefit from atezolizumab plus bevacizumab in hepatocellular carcinoma.

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Background: Atezolizumab plus bevacizumab (A+B) improves survival compared with sorafenib (Sora) in advanced hepatocellular carcinoma (HCC), yet predictive biomarkers remain undefined. Laminin γ2 monomer (LG2m) is expressed in CD90-positive stem-like HCC cells. We investigated whether LG2m reflects an immunosuppressive tumor microenvironment (TME) and modifies survival benefit from A+B. Methods: Single-cell spatial analysis (PhenoCycler) was performed in resected HCC specimens to characterize CD90-positive tumor cells and immune cell distribution according to LG2m expression. In advanced HCC (n=135; A+B n=85, Sora n=50), serum LG2m was measured using chemiluminescent immunoassay. A cutoff of 49.3 pg/mL was applied. Progression-free survival (PFS) and overall survival (OS) were analyzed. Results: Spatial analysis revealed that LG2m-high tumors showed dense accumulation of CD90-positive cells at the tumor boundary, enrichment of CD206-positive macrophages, and reduced infiltration of activated CD4⁺ and CD8⁺ T cells, consistent with an immunosuppressive niche. In the overall cohort, A+B significantly improved PFS (HR 0.45; P<0.001) and OS (HR 0.50; P=0.003) compared with Sora. However, stratified analysis demonstrated effect modification by LG2m. In LG2m-low patients, A+B markedly improved PFS (HR 0.33; P<0.001) and OS (HR 0.27; P<0.001). In contrast, in LG2m-high patients, A+B did not show superiority over Sora for either PFS (HR 0.65; P=0.15) or OS (HR 0.78; P=0.48). Conclusions: LG2m identifies an immunosuppressive, CD90-driven TME and delineates a subgroup of HCC patients in whom survival benefit from A+B is attenuated. Serum LG2m may serve as a clinically actionable biomarker to refine immunotherapy selection in advanced HCC.