A Novel Target in The Tumor Myeloid Compartment for Hepatocellular Carcinoma

PROJECT 3: SUMMARY Given the limited clinical benefits of the current treatments for hepatocellular carcinoma (HCC), there is an urgent need for novel approaches to improve patient outcomes. This project seeks to understand the host molecular determinants in immune surveillance and therapeutic responsiveness of HCC by focusing on the innate pattern recognition receptor SRA/CD204 that is primarily expressed on cells of myeloid origin. In this project, we will test the hypothesis that SRA acts as a previously unrecognized immune checkpoint on myeloid cells by impairing immune recognition during hepatocarcinogenesis and facilitating therapeutic resistance particularly to immune checkpoint inhibitors (ICIs). This hypothesis is supported by our preliminary data showing increased immune-mediated regression of HCC and HCC susceptibility to anti-PD-1 therapy in the absence of SRA. The overall goals of this project are to examine SRA-centric molecular pathways within the myeloid cell compartment of the tumor microenvironment that promote immune tolerance and develop novel combination strategies using therapeutic antibodies for SRA to achieve durable control of HCC. To accomplish the objectives, we will first establish a critical role of SRA for promoting cancer-immune evasion using mouse models of HCC including the oncogene MYC-driven hepatocarcinogenesis as well as experimental tools that we have generated (e.g., an SRA conditional knockout mouse). Additionally, we will mechanistically understand the SRA function in defining HCC responsiveness to ICI-based immunotherapy. Considering the T- cell suppressive activity of a soluble form of SRA, we will also examine its alteration during disease progression in mouse models and in human HCC. Lastly, we will evaluate SRA-targeting antibody blockade as a novel means to reinvigorate immune activation that can be rationally combined with ICIs and/or targeted therapy (e.g., MYCi975) for safe and effective HCC control. It is anticipated that successful completion of the proposed research via synergistic collaborations with other projects of the ELEVATE P01 will help fill the scientific gap in understanding host molecular components that can govern cancer-immune escape and treatment resistance. Importantly, validation of blocking antibodies for SRA may lead to an innovative strategy to reprogram the immune landscape of HCC and improve the treatment outcomes for patients.