Infiltration of immunosuppressive myeloid population in hypoxic area of hepatocellular carcinoma determines its response to anti-PD1 therapy 2519

Abstract Description Hepatocellular carcinoma (HCC) is a major public health challenge and the most common primary liver cancer in adults globally. Anti-PD1 therapy is a standard treatment for HCC, but its effectiveness varies. Immunosuppressive population play a crucial role. Our study used single-cell spatial transcriptomic analysis to map these cells in the tumor microenvironment of HCC patients who do not respond to anti-PD1. We found that macrophages and monocytes cluster around the tumor boundary in non-responders, with enriched immunosuppressive signaling pathways and higher cancer cell proliferation. Hypoxia markers were enriched in both responder and non-responder groups, with denser macrophage and monocyte populations in hypoxic areas, especially at the fibrotic and carcinoma tissue interface. In non-responders, hypoxic regions correlated with elevated TGFβ signaling, ROS, IL6, apoptosis, and angiogenesis expression, while other areas showed high glycolysis expression. These patterns were absent in responders. In vitro experiments with bone marrow-derived monocytes and macrophages under hypoxic conditions showed increased immunosuppressive abilities, including suppression of CD8+ cytotoxic T cell activation and function, along with elevated glycolysis. Inhibiting glycolysis in hypoxic myeloid cells reduced their immunosuppressive function. Our findings suggest that immunosuppressive myeloid cell infiltration in hypoxic areas of HCC is key to the response to anti-PD1 therapy. Funding Sources Supported by Health and Medical Research Fund (Ref. No.: 19201591) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)