Tina (Heng-Jia) Liu, PhD
Heng-Jia Liu, Heng Du, Damir Khabibullin, Mahsa Zarei, Kevin Wei, Gordon J. Freeman, David J. Kwiatkowski, Elizabeth P. Henske
Heng-Jia Liu & Elizabeth P.
Research Category: Cancer
Immune checkpoints are often expressed on tumor cells, it remains a prevailing need to identify the mechanisms underlying their regulation and therapeutic benefit. Analysis of 11,060 TCGA human tumors representing 34 subtypes revealed that high expression of a key immune checkpoint, B7-H3 (CD276), and high mTORC1 activity correlate with immunosuppressive phenotypes and worse clinical outcomes. We found that mTORC1 regulates B7-H3 expression via phosphorylation the transcription factor YY2 by S6K. Inhibition of B7-H3 suppresses mTORC1-hyperactive tumor growth via an immune-mediated mechanism that involves increased T-cell activity and IFN-γ responses coupled with increased tumor cell expression of MHC-II. CITE-seq at the single-cell resolution revealed strikingly increased cytotoxic CD38+CD39+CD4+ T cells in B7-H3-deficient tumors. In pan-human cancers, a high cytotoxic CD38+CD39+CD4+ T-cell gene signature correlates with better clinical prognosis. These results show that mTORC1-hyperactivity, which is present in many human tumors, drives B7-H3 expression leading to suppression of cytotoxic CD4+ T cells.
This project is focused on using the body’s own immune system to treat tumors, referred to as “immunotherapy”. White blood cells (WBCs) are cells of our immune system that are involved in protecting the body against foreign invaders and eliminating abnormal cells, including tumor cells. However, WBCs within tumors are often prevented from recognizing and destroying tumor cells. This occurs in part because of specific proteins in tumor cells inhibit the ability of “killer T cells” (a specialized type of WBC that kills tumor cells) to eliminate tumor cells. In dramatic breakthroughs in the past 12 years, it has been discovered that the tumor-fighting ability of killer T cells can be restored by using antibody-based targeted therapies (a type of immunotherapy), and that the approach can eliminate tumor cells.
My studies show that targeting the specific protein B7-H3 in tumors will restore the tumor-fight ability of killer T cells, allowing them to eliminate tumor cells. Monoclonal antibodies against B7-H3 have already been used for human clinical trials, with no dose-limiting toxicities. The potential risks of anti-B7-H3 antibody, therefore, appear to be less than other immune-focused therapies. At least twelve B7-H3 targeted cancer clinical trials are currently ongoing (ClinicalTrials.gov).