Beyond personal hygiene, the most impactful public health innovation in human history has been the development of vaccines, which has allowed many scourges of humanity, such as smallpox, to been eradicated or reduced to clinical inconsequentiality. However, the use of vaccines has largely been restricted to preventing infections. Cancer vaccines have long-been envisioned, with limited success. Hepatocellular carcinoma (HCC) is the most common liver tumor and among the deadliest cancers worldwide. Unfortunately, HCC is largely impervious to widely used T cell-directed immunotherapies such as PD-1 and CTLA4 inhibitor, likely due to the relatively immunotolerant nature of the disease. My goal is to leverage novel concepts in innate immunity to generate vaccines against HCC. Dendritic cells (DCs) are a promising immunotherapeutic modality given their unique ability to induce robust and durable antigen-specific T cell responses. Classical DC stimuli such as lipopolysaccharide (LPS) can only stimulate a subset of activities essential for DC function. A second signal, such as the oxidized phospholipid PGPC, is needed to maximally stimulate DCs into an “hyperactive” state that engender robust and durable T cell responses. We hypothesized that vaccinations with hyperactivated DCs can confer superior anti-tumor immunity. To test this hypothesis, we adopted a genetically-engineered mouse model (GEMM) of HCC that recapitulates human disease. Immunization of tumor-bearing mice subcutaneously with OVA (an neoantigen expressed by the tumor) and DC hyperactivating molecules (LPS plus PGPC) led to reduced tumor burden and lethality, compared to other adjuvants. Similar protective results were seen in mice that were immunized with murine primary DCs that were loaded with OVA and hyperactivated with LPS and PGPC ex vivo (Figure 1). Thus, using classic immunizations or adoptive DC transfers, we provide the first example of a successful innate immune vaccination against a GEMM model of cancer. Tumors isolated from mice treated with hyperactivated DCs showed an enrichment of antigen-specific CD8+ T cells with more robust IFNg production, a cytokine essential for anti-tumor immunity (Figure 2a,b). Antigen-specific IFNg production persisted up to 120 days post-tumor induction, and was associated with a larger number of tissue resident and circulating memory CD8+ T cells, supporting the potential for DC hyperactivating stimuli to induce long-lived memory responses (Figure 2c-e). Furthermore, we found that hyperactive DC treatments resulted in a smaller proportion of intratumoral antigen-specific CD8+ T cells expressing markers of dysfunction, such as PD-1 (Figure 2f). Our study offers a novel cancer vaccine strategy that leverages our innate immune system to overcome challenges faced by conventional T-cell based therapies in treating HCC and other immunotolerant tumors.

Jonathan Kagan

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