An immune-related pathologic response score as a predictor of survival after immune checkpoint inhibitor–based conversion therapy in hepatocellular carcinoma.

4162 Background: Immune checkpoint inhibitor (ICI) based conversion therapy is increasingly utilized in the management of initially unresectable hepatocellular carcinoma (HCC). However, the clinical significance of immune-related pathologic response (irPR) features remain poorly understood in HCC. Methods: We enrolled 217 HCC patients undergoing ICI-based conversion therapy followed by curative-intent resection and assigned them to discovery and validation cohorts (2:1). Thirteen immune-related pathological response (irPR) features—tumor-infiltrating lymphocytes, tertiary lymphoid structures, lymphoid aggregates, plasma cell infiltration, granulomas, neutrophils, foamy macrophages, cholesterol clefts, hemosiderin-laden macrophages, giant cells, neovascularization, necrosis, and mature fibrosis—were assessed on H&E-stained tumor bed sections. To explore differences in the tumor microenvironment, bulk mRNA sequencing was performed on FFPE samples from patients in the discovery cohort. Results: In the discovery cohort, four irPR features (tumor-infiltrating lymphocytes, lymphoid aggregates, neutrophils, and foamy macrophages) were integrated to construct the immunotherapeutic response score (ITRS), classifying patients as ITRSlow (0–1) or ITRShigh (2–4). ITRS low patients showed significantly improved OS (HR = 4.17; 95% CI 1.64–10.60; P = 0.003) and RFS (HR = 2.07; 95% CI 1.32–3.23; P = 0.001), with longer median RFS (32.3 vs 8.5 months). ITRS remained independently associated with OS (HR = 2.81; 95% CI 1.06–7.43; P = 0.038) and RFS (HR = 2.10; 95% CI 1.32–3.33; P = 0.002) and was validated in an independent cohort. FFPE transcriptomic profiling (n = 41) showed that ITRS low tumors were immune-inflamed, with enrichment of immune-related GO/KEGG pathways and globally higher immune/stromal infiltration (higher ESTIMATE immune/stromal scores, lower tumor purity; all P < 0.001). Unsupervised clustering identified hot/cold states, with hot tumors enriched in ITRS low (65.4% vs 13.3%, P = 0.003); CD8 + T-cell infiltration was higher across MCPcounter/CIBERSORT/TIMER and was accompanied by stronger antigen presentation (MHC-II gene sets) and increased CD8 + T-cell activation/cytotoxicity as well as exhaustion signatures (all P < 0.05), supporting an immune-active microenvironment linked to favorable outcomes. Conclusions: An irPR feature–based ITRS robustly predicts both OS and RFS in HCC patients following ICT. The ITRS is readily applicable in routine diagnostic pathology practice and provides novel insights into the biological mechanisms underlying immunotherapy resistance.