Research
Our Motivation
Targeted therapy and immunotherapy have revolutionized the field of cancer therapy in the past decade, especially for blood cancers, which is evidenced by the FDA approval of several targeted therapies (e.g., venetoclax, gilteritinib) and cellular immunotherapies (e.g., CAR T cells, TCR T cells) for certain types of blood cancers. However, a substantial subset of patients does not respond to these therapies or develops resistance.
These clinical observations highlight the unmet need for dissecting cancer-associated drug resistance and immune evasion mechanisms, establishing their connections with treatment efficacy and reversing these pro-cancer events to improve patient outcomes.
Figure 1. The guiding principle of our research
Our Research Principle
Our research principle is to discover therapeutic targets that address clinical needs using comprehensive screening approaches (A), followed by mechanistic studies to reveal underlying mechanisms (B) and uncover potential targeting strategies that may ultimately be translated into the clinical arena (C).
Figure 2. Cell intrinsic and extrinsic mechanisms for AML-associated drug resistance and immune evasion
Our Contributions
Our previous research discovered CLPB and MFN2 as two mitochondrial dynamic regulators, whose ablation strongly sensitizes acute myeloid leukemia (AML, the most devastating blood cancer) blasts to venetoclax (BCL2 inhibitor), an FDA-approved BH3-mimetic drug that induces apoptosis. It sensitizes them by disrupting mitochondrial cristae remodeling and mitochondria-endoplasmic reticulum (mito-ER) interactions (A and B, Cancer Discovery, 2019, 2023). These studies shed light on the cell-intrinsic mechanisms of BH3-mimetics resistance in AML and suggest that targeting mitochondrial dynamics could be a promising strategy to overcome BH3-mimetics resistance.
Apart from cell-intrinsic mechanisms, we also identified a novel antigen presentation (AP) inhibitory axis that comprises two transmembrane proteins (SUSD6 and TMEM127) and the E3 ligase WWP2. This axis substantially suppresses cancer immunogenicity by inhibiting MHC-I surface expression, which in turn abrogates anti-cancer immunity (C, Cell, 2023). In addition, through T cell cytotoxicity-based screenings, we identified a transcriptional regulator IRF2BP2, whose inhibition restores cancer immunogenicity and potentiates TCR-T therapies (D, ongoing project). Collectively, these findings not only advance our understanding of immune recognition and evasion mechanisms but also provide promising candidates for cancer immunotherapy.
Figure 3. Decoding the immune networks and advancing therapeutic intervention to overcome treatment resistance and potentiate anti-cancer immunity
Our Future Plans
Our experience emphasizes that the complexity of drug resistance and immune suppression mechanisms stems from the dysregulation of not only the endogenous abnormalities but also the cancer-immune cell interactions within the cancer immune microenvironment (IME). We therefore aim to:
- Decode the intricate networks that contribute to drug resistance and immune suppression in blood cancer, especially in AML
- Explore the fundamental principles of intercellular communication between immune cells and cancer cells to fine-tune anti-cancer immunity
Examples of projects in our laboratory include:
- Unleashing cancer immunogenicity to potentiate immunotherapy
- Dissecting the cancer-immune co-evolving events to dictate immunotherapy outcomes
- Systematic and functional profiling of the interactions between AML and its IME (A)
- Developing new target discovery platforms for next-generation immunotherapy
- Translating our insights into the development of novel therapeutic strategies to circumvent treatment resistance and exploit anti-cancer immunity (B)