My laboratory has been engaged in basic and translational cancer research in the field of cancer genomics, targeted cancer therapy and immunotherapy. My current study is focused on (1) Identification of new therapeutic targets that drive immune evasion in triple negative breast cancer. (2) Identification of epigenetic inhibitors that enhance tumor antigen presentation using patient-derived organoids.
Triple negative breast cancer (TNBC) are highly aggressive, metastatic, and with the worst prognosis among all types of breast cancers, but no targeted therapy is now available for TNBC. Cancer immunotherapy, notably immune-checkpoint blockade, has shown promise in treating patients with TNBC, but the response rates are up to 10% in unselected TNBC patients and only improves slightly even when patients are selected based on the tumor positivity of PD-L1. There is unmet need to understand potential mechanisms for immune evasion in TNBC.
Anti-tumor immune responses require functional presentation of tumor antigens and a microenvironment that favors competent immune effectors. Increased antigen presentation on tumor cells can be of therapeutic significance since it makes tumor cells more susceptible to the cytotoxic T lymphocytes. In the preliminary study, we identified a membrane protein, MAL2, as an important player that determines the turnover of the antigen-MHC-I complex and reduces the antigen presentation on breast cancer cells. In preclinical models, inhibition of MAL2 profoundly enhanced the cytotoxicity of tumor-infiltrating CD8+ T cells and suppressed breast tumor growth. This part of work was published in Journal of Clinical Investigation in 2021 and was selected as the cover story recently.
Epigenetic modification of MHC-I has been observed in a range of cancers and has recently been identified as a mechanism of resistance to immunotherapy. To identify epigenetic inhibitors that enhance tumor antigen presentation and potentiate T cell-mediated cytotoxicity in TNBC, we developed a high-throughput screen approach based on the functional interaction of cytotoxic T cells with 3D breast tumor organoids that resemble the histology of the original tumors. Several epigenetic inhibitors have been identified from the screen and their anti-tumor activities were validated by in vivo tumor models. Part of the work was published in Nature BME in 2021.