{"doi":"10.1002/cac2.12421","title":"Advanced precision modeling reveals divergent responses of hepatocellular carcinoma to combinatorial immunotherapy","abstract":"Dear Editor Combinatorial immunotherapy has provided patients with advanced hepatocellular carcinoma (HCC) the potential for long-term survival. However, sustained responses are seen only in a minority of patients [1]. Thus, there is an unmet need for precision modeling to understand the different responses and uncover predictive biomarkers for treatment stratification. Here, we investigated the responses of HCC to combinatorial immunotherapy in two genetic mouse models, N90-CTNNB1OE;TP53KO and MycOE;TGFαOE mice, which produce overexpression of an activated form of β-catenin (CTNNB1) together with deletion of tumor protein 53 (TP53) or overexpression of the MYC oncogene together with transforming growth factor α (TGFα), respectively. Mutations in these pathways are frequently present in human HCC. We found that the two models of HCC displayed remarkably distinct immune landscapes (Figure 1A, Supplementary Figures S1-S2). Multi-locular tumors developed rapidly (less than 3 months) in both models (Figure 1A, Supplementary Figure S1E). Remarkably, the Myc-driven MycOE;TGFαOE tumors were immunologically “cold” and exhibited high proliferation rates, while N90-CTNNB1OE;TP53KO tumors were immunologically “hot” and showed elevated levels of vascularization and immune cell infiltration (Supplementary Figures S1-S2). Given the increased expression of vascular endothelial growth factor (VEGF) and programmed cell death-ligand 1 (PD-L1) in the N90-CTNNB1OE;TP53KO model (Supplementary Figure S2), we investigated if there are distinct responses of the two HCC models to combinatorial immunotherapy. We administered lenvatinib, a multi-tyrosine kinase inhibitor that inhibits both the VEGF and tumor fibroblast growth factor receptor pathways together with anti-programmed cell death protein 1 (PD-1) antibodies to N90-CTNNB1OE;TP53KO or MycOE;TGFαOE mice with fully established tumors (Supplementary Figure S3A). Remarkably, the combinatorial immunotherapy significantly reduced the burden of large tumors ( ≥ $ \\ge \\;$ 2 mm-size) compared with IgG isotype control in N90-CTNNB1OE;TP53KO animals, but not in the MycOE;TGFαOE -driven model (Figure 1A, Supplementary Figure S3). Thus, immunologically “hot” N90-CTNNB1OE;TP53KO tumors responded more to combinatorial immunotherapy than immunologically “cold” MycOE;TGFαOE tumors. Next, we investigated the hepatic response to combinatorial immunotherapy in both models in detail by immunofluorescence staining with the B cell marker CD45R and the CD8+ T marker CD8A in combination with Ki67 to assess proliferation and T and B cell activation status. Strikingly, we found that immune cell clusters in the N90-CTNNB1OE;TP53KO model contained tertiary lymphoid structures (TLSs) with B cell follicle and T cell zones after combinatorial immunotherapy (Figure 1B; Supplementary Figure S4). Notably, of the 93 TLSs observed in our study, 88 were located in the tumor periphery, while only 5 were present within the tumor itself (data not shown). A large proportion of follicular B cells were Ki67 positive (74.8% for treatment versus 27.8% for IgG isotope control) in TLSs of CTNNB1OE;TP53KO mice, indicating their high activation state (data not shown). In contrast, the Myc/TGFα-driven tumors exhibited very few TLSs (Figure 1B). Collectively, the less proliferative N90-CTNNB1OE;TP53KO tumors were responsive to combinatorial immunotherapy, which was associated with an augmented TLS response. To better understand the distinct responses of the two HCC models to combinatorial immunotherapy, we employed NanoString technology to perform immune transcriptomic profiling of N90-CTNNB1OE;TP53KO- and MycOE;TGFαOE-driven tumors with or without combinatorial immunotherapy. Notably, the expression of genes relevant to the TLS response was highly elevated in the N90-CTNNB1OE;TP53KO-driven tumor model (Figure 1C, Supplementary Figure S5). We next focused on ten differentially expressed TLS genes previously recognized as crucial for TLS formatio","journal":"Cancer Communications","year":2023,"id":388091,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9534,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1005730,"name":"Lan Cheng","orcid":"0009-0007-1084-7159","position":1,"is_corresponding":false},{"id":1005731,"name":"Hilana El‐Mekkoussi","orcid":"0000-0001-5561-4358","position":2,"is_corresponding":false},{"id":94285,"name":"Charles-Antoine Assenmacher","orcid":"0000-0003-0073-2730","position":3,"is_corresponding":false},{"id":650172,"name":"Michelle Y. Y. Lee","orcid":"0000-0002-5574-8011","position":4,"is_corresponding":false},{"id":1006436,"name":"Danielle R. Jaffe","orcid":null,"position":5,"is_corresponding":false},{"id":1157713,"name":"Kaisha Garvin‐Darby","orcid":null,"position":6,"is_corresponding":false},{"id":252941,"name":"Ashleigh Morgan","orcid":null,"position":7,"is_corresponding":false},{"id":14811,"name":"Elisabetta Manduchi","orcid":"0000-0002-4110-3714","position":8,"is_corresponding":false},{"id":650174,"name":"Jonathan Schug","orcid":"0000-0001-6885-7869","position":9,"is_corresponding":false},{"id":250526,"name":"Klaus H. Kaestner","orcid":"0000-0002-1228-021X","position":10,"is_corresponding":false},{"id":1157352,"name":"Jinping Liu","orcid":"0000-0002-8669-882X","position":0,"is_corresponding":true}],"reference_count":8,"raw_metadata":null,"created_at":"2026-07-19T01:18:13.977537Z","pmid":"37037491","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}