Abstract 6140: Therapeutic benefits of innate immunity stimuli in hepatocellular carcinoma

Abstract Beyond personal hygiene, the most impactful public health innovation in human history has been the development of vaccines to protect against lethal infections. Cancer vaccines have long-been envisioned, with minimal clinical success. Hepatocellular carcinoma (HCC) is the most common liver tumor and one of the leading causes of cancer-related mortality worldwide. Unfortunately, most HCC patients fail to respond to widely used T-cell based immunotherapies, likely due to the relatively immunotolerant nature of the disease. Thus, there is an urgent need to develop more effective therapies against HCC. Dendritic cells (DCs) are an attractive immunotherapeutic target given their unique ability to induce anti-tumor T cell responses. Various key DC activities are needed for this function, including migration to draining lymph nodes, tumor antigen presentation, co-stimulation, and production of inflammatory cytokines like interleukin (IL)-1β. Conventional DC stimuli, such as the Toll-Like Receptor ligand lipopolysaccharide (LPS), activate only a subset of these activities. For instance, production of IL-1ß, a cytokine important for memory T cell function, requires a second signal that activates the NLRP3 inflammasome. Commonly used adjuvants that activate NLRP3 inflammasomes and induce IL-1ß release also trigger cell death, undermining the ability for DCs to engage in the other activities required for T cell stimulation. Our lab discovered that the oxidized phospholipid PGPC (1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine) can augment IL-1ß release and migration of DCs while maintaining viability, generating a “hyperactive” DC (hDC) state that engender superior T cell responses compared to conventionally activated DCs. To study the anti-tumor benefits of hDCs, we adopted a genetically engineered mouse model of HCC that highly recapitulates human disease. We show that subcutaneous immunizations with hDCs suppress tumor growth and lethality, and that this protective phenotype is NLRP3-dependent. We also show that hDCs are uniquely able to traffic from the subcutaneous immunization site into the liver. Tumors isolated from hDC-immunized mice have an enrichment of antigen-specific CD8+ T cells with more robust IFNγ-production. Furthermore, hDC treatment resulted in a smaller proportion of antigen-specific CD8+ T cells expressing markers of dysfunction, such as PD-1. Remarkably, at 120 days post-tumor induction, there were more antigen-specific tissue resident memory T cells in the livers of mice previously treated with hDCs, and more of these T cells retained the capacity for antigen-specific IFNγ production. Our project demonstrates how novel concepts in innate immunity can be leveraged to engender more potent and durable anti-tumor T cell responses, and to generate vaccines against HCC that can overcome common limitations of conventional immunotherapies. Citation Format: Longyue Lily Cao, Jonathan Kagan. Therapeutic benefits of innate immunity stimuli in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6140.