Δ42PD-1 inhibitor acts as a PD-1-independent immunotherapy against human hepatocellular carcinoma

Abstract

Abstract Pathogen infection-induced chronic inflammation is a key contributor to both carcinogenesis and progression of hepatocellular carcinoma (HCC). Persistent toll-like receptor 4 (TLR4) signaling activation can lead to inflammatory responses and chronic inflammation in the tumor microenvironment. Previously, Δ42PD1, a PD1 isoform, has been shown to directly interact with its cognate receptor TLR4 and contribute to innate immune activation and intestinal pathogenesis during acute HIV-1 infection. Here, we aim to determine whether such interaction may also occur in HCC to promote TLR4 signaling activation and in turn induce inflammatory responses, contributing to HCC progression. We studied the relationship between TLR4, Δ42PD1, pro-inflammatory cytokines and tumor development in humanized mouse models and HCC patients. In consistence with others’ findings, TLR4 signal was shown to be associated with chronic inflammation and HCC tumor progression. Furthermore, we demonstrated that Δ42PD1 activated TLR4-mediated inflammatory responses in HCC cells via cJUN MAPK transcriptional activation. Notably, Δ42PD1-TLR4 pathway activation likely formed a feedback loop to induce Δ42PD1-expression CD3+ T cells, a new phenotype of T cell exhaustion, further contributing to tumor development. Importantly, administration of a Δ42PD1-specific monoclonal antibody CH101 interrupted Δ42PD1-TLR4 pathway and displayed therapeutic efficacy in both subcutaneous and orthotopic HCC models. Together, our results demonstrated the importance of Δ42PD1-TLR4-mediated inflammatory responses in promoting HCC and provided conclusive evidence that targeting Δ42PD1-TLR4 pathway reduced inflammatory responses to arrest HCC development.