Targeting a Novel Secreted Immune Checkpoint to Enhance Liver Cancer Immunotherapy - PROJECT SUMMARY/ABSTRACT Liver cancer, particularly hepatocellular carcinoma (HCC), is a leading cause of cancer-related deaths globally and one of the fastest-growing cancers in the United States. Despite the approval of immune checkpoint inhibitors (ICIs) for advanced HCC, most patients experience unsatisfactory therapeutic outcomes due to the immunosuppressive tumor immune microenvironment (TiME) in HCC, which limits effective T cell responses. Our long-term goal is to understand the mechanisms underlying cytotoxic T cell suppression and resistance to ICIs, and to identify potential drug candidates for combination therapy with ICIs or innovative strategies to improve the outcomes of adoptive T-cell therapy. The objective of this proposal is to investigate how the LIFR- LCN2 pathway in liver cancer restricts the cytotoxic function of CD8+ T cells to lead to immune evasion and resistance to immunotherapy. The proposed work is strongly supported by our preliminary studies: 1) Acquired resistance to PD-1 blockade correlates with decreased Lifr and increased Lcn2 levels; 2) LIFR overexpression suppresses HCC in a CD8+ T cell-dependent manner; and 3) the LIFR-LCN2 pathway inhibits the activity of CD8+ T cells. Our central hypothesis is that loss of LIFR upregulates LCN2 in liver cancer, thereby suppressing the abundance and cytotoxic function of CD8+ tumor-infiltrating lymphocytes (TILs) through MC4R, leading to immune evasion and resistance to immunotherapy. Our rationale is that uncovering the mechanisms behind the suppressed cytotoxic function of CD8+ TILs in the hostile TiME of liver cancer will open up new therapeutic opportunities for liver cancer patients. The central hypothesis will be tested by pursuing two specific aims: (Aim 1) Investigate whether the LIFR-LCN2 pathway inhibits the effector function of CD8+ T cells; (Aim 2) Determine strategies to target LCN2-MC4R signaling to enhance immunotherapy. This study is significant due to its potential to reveal novel mechanisms of immune suppression in liver cancer and identify new therapeutic targets. Our findings suggest that LCN2 functions as a ‘‘secreted immune checkpoint’’ that hampers anti-tumor immunity, indicating that inhibiting LCN2-MC4R signaling could be a valuable strategy to enhance liver cancer immunotherapy. The proposed research is innovative in its exploration of a novel immune regulatory pathway in HCC, its potential to enhance the efficacy of ICIs and CAR-T cell therapy through combined therapeutic strategies, and its integration of mechanistic insights with translational research approaches.
