Titles + affiliations
Instructor, Department of Pathology
New York University School of Medicine
Research
Targeting Antigen Presentation for Next-Generation Immunotherapy of Acute Myeloid Leukemia
Summary
Acute myeloid leukemia (AML) is a devastating blood cancer. Although the revolutionary discovery of immunotherapies, designed to boost the immune system to eliminate cancer cells, has saved thousands of lives, this brilliant method doesn’t seem to work well in the treatment of AML patients. One potential reason is that “smart” AML cells can pretend to be normal cells to avoid being recognized by the immune system through masking their tumor antigens (the “ID” of AML cells). Thus, it is necessary to understand how AML can reduce the presentation of tumor antigens and to identify those AML-derived antigen presentation regulators in order to offer novel immunotherapy options for AML patients. Using systematic screening approaches, we have identified IRF2BP2 as one of these regulators. IRF2BP2 potently suppresses antigen presentation in AML. Notably, ablation of IRF2BP2 can facilitate immune cell-mediated elimination of AML. In this proposal, we seek to comprehensively investigate how this protein regulates tumor antigen presentation in AML. Moreover, this study aims to test the feasibility of combining IRF2BP2 inhibition and existing frontline immunotherapies from a therapeutic perspective. Our proposed studies will not only advance our knowledge of AML-associated regulation of antigen presentation but also provide new candidates for next-generation cancer immunotherapy, that may offer a better therapeutic option to patients with poor responses to current therapies.
Impact
The original purpose of this project was to comprehensively and systematically identify functional immunosuppressive AP regulators in AML, which could provide invaluable information for improving the efficacies of immunotherapies in AML, the most devastating leukemia with very limited immunotherapeutic options. With the grant support from Leukemia Research Foundation, we have completed the majority of the proposed aims and we confirmed that ablation of IRF2BP2 can enhance the immunogenicity of AML cells by restoring their antigen presentation capacity. Therefore, IRF2BP2 inhibition can potentiate T cell activation and function. Consistently, IRF2BP2 depletion can enhance T cell-mediated immune surveillance, suppress AML progression, and prolong animal survival in pre-clinical animal models, which is further supported by several clinical evidence.
Based on our findings in this project, plus the high expression of IRF2BP2 in AML and the advance in drug targeting/delivery technologies, we are convinced that IRF2BP2 is a potential therapeutic target that could restore AML-specific T cell immunity, which could be combined with existing frontline immunotherapies to overcome the non-responsiveness and drug resistance. Since immunotherapies are becoming frontline options for various malignancies, such combinatorial treatments could save the lives of a large number of patients with poor responses to current immunotherapies.
Taken together, our study advances our understanding of AML-associated immune evasion of the MHC-I AP pathway and provides promising candidates for AML immunotherapy. In addition, these findings may even be extended beyond AML to solid tumors with cold tumor microenvironments, as AP inhibition could be a universal immune-evasion mechanism.
Publications:
AACR special conference: acute myeloid leukemia and myelodysplastic syndrome: https://aacrjournals.org/bloodcancerdiscov/article/4/3_Supplement/A10/725993/Abstract-A10-Targeting-MHC-I-antigen-presentation
Cell (journal): https://pubmed.ncbi.nlm.nih.gov/37557169/
Leukemia Research Foundation grant
$100K awarded in 2022
Disease focus
Acute myeloid leukemia (AML)
Research focus
Treatment (immunotherapy)