| Contributors: |
Scheiner, B.; Lombardi, P.; D'Alessio, A.; Kim, G.; Tafavvoghi, M.; Petrenko, O.; Goldin, R. D.; Fulgenzi, C. A. M.; Torkpour, A.; Balcar, L.; Mauri, F. A.; Pomej, K.; Himmelsbach, V.; Barsch, M.; Celsa, C.; Cabibbo, G.; Cheon, J.; Krall, A.; Hucke, F.; Di Tommaso, L.; Bernasconi, M.; Rimassa, L.; Samson, A.; Stefanini, B.; Mozayani, B.; Trauner, M.; Lackner, C.; Stauber, R.; Vasuri, F.; Piscaglia, F.; Bengsch, B.; Finkelmeier, F.; Peck-Radosavljevic, M.; Rasmussen Busund, L. -T.; Marafioti, T.; Rahbari, M.; Heikenwalder, M.; Pinter, M.; Chon, H. J.; Rakaee, M.; Pinato, D. J. |
| Description: |
Spontaneously immunogenic hepatocellular carcinoma (HCC), identified by a dense immune cell infiltrate (ICI), responds better to immunotherapy, although no validated biomarker exists to identify these cases. We used machine learning (ML) to quantify ICI from standard H&E-stained tissue and evaluated its correlation with characteristics of the tumor microenvironment (TME) and clinical outcome from atezolizumab plus bevacizumab (A+B). We therefore employed a supervised ML algorithm on 102 pretreatment H&E slides collected from patients treated with A+B. We quantified tumor, stroma and immune cell counts/mm2 and dichotomized patients into ICI high and ICI low for clinicopathologic analysis. We correlated ICI signature with characteristics of the T-cell infiltrate (CD4+, FOXP3+, CD8+, PD1+) using multiplex immunohistochemistry in 62 resected specimens and evaluated gene expression profiles by bulk RNA sequencing in 44 samples. All patients treated with A+B were Child-Pugh A and received first-line A+B treatment for Barcelona Clinic Liver Cancer Stage C HCC (n=77, 75.5%) on a background of viral (n=53, 52%) and non-viral (n=49, 48%) liver disease. Median ICI density was 429.9 (IQR: 194.6–666.7) cells/mm2. Two-thirds of patients (n=67, 65.7%) had ICI counts≥236/mm2, derived as the optimal prognostic cut-off (ICI-high). Baseline characteristics, including disease etiology, liver function, performance status, stage, prior therapy and alpha-fetoprotein (AFP) levels, were comparable between ICI-high versus ICI-low patients. Patients with ICI-high demonstrated a significantly longer overall survival (OS) compared with ICI-low: 20.9 (95% CI: 13.8 to 27.9) versus 15.3 (95% CI: 6.0 to 24.6 months, p=0.026). Multivariable analyses demonstrated ICI-low status to remain as an independent prognostic parameter (adjusted HR (aHR): 2.02, 95%CI: 1.03 to 3.96) alongside AFP concentration (per 100ng/mL: aHR 1.00, 95%CI: 1.00 to 1.00). ICI-high tumors were characterized by STC1 underexpression and enrichment in proinflammatory ... |