Abstract B013: Evaluation of anti-PD-L1 and anti-VEGF-A combinatorial immunotherapy in preclinical murine liver cancer models

Abstract The combination of Atezolizumab (anti-PD-L1) plus Bevacizumab (anti-VEGF-A) is the most up-to-date FDA-approved first-line therapy for advanced stage hepatocellular carcinoma (HCC). Although this immune-oncology intervention showed better overall and progression-free survival, it only elicits a response in 20 – 30% of patients. Moreover, prognostic and predictive markers are currently unavailable, which renders patient stratification infeasible. In light of this obstacle, it is imperative to investigate the underlying mechanisms that drive therapeutic resistance. In this study, we aim to understand how genetic mutation background and etiology could impact therapeutic response. We evaluated the effects of anti-PD-L1 and anti-VEGF-A in different spontaneous liver cancer mouse models, with three gene-editing-based murine liver cancer models, and a diet-based murine metabolic dysfunction-associated steatohepatitis-induced HCC (MASH-HCC) model. The immunological landscape was examined with histological analysis, flow cytometry, and single-cell RNA sequencing (scRNA-seq). We demonstrated that the combinatorial immunotherapy significantly reduced tumor burden in c-Myc/Tp53-/--driven HCC, accompanied by an increase of CD8 T cells. However, the same therapy failed to inhibit tumor progression in KrasG12D/Tp53-/--driven combined hepatocellular and intrahepatic cholangiocarcinoma (cHCC-ICC), Ctnnb1T41A/c-Myc-driven HCC, and MASH-HCC, with a limited stimulation of CD4 and CD8 T cell infiltration and activation. Moreover, we found that the combinatorial immunotherapy induced an increase in tumor-associated neutrophils (TANs) in cHCC-ICC, and the auto-aggressive PD1+ CD8 T cell population in MASH- HCC, which likely take part in the development of therapeutic resistance. In summary, our findings suggest that both mutational background and etiology could influence the response of anti-PD-L1 and anti-VEGF-A combinatorial therapy, which might be attributed to the distinct immune microenvironment. Citation Format: Shing Kam, Pierluigi Ramadori, Chaofan Fan, Sagar Sagar, Mathias Heikenwälder. Evaluation of anti-PD-L1 and anti-VEGF-A combinatorial immunotherapy in preclinical murine liver cancer models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B013.