Abstract A10: Targeting MHC-I antigen presentation for cancer immune evasion in acute myeloid leukemia
Authors: Chen Xufeng , Lu Qiao , Zhou Hua , Liu Jia , Nadorp Bettina , Lasry Audrey , Sun Zhengxi , Zhang Jiangyan , Cammer Michael , Wang Kun , Ciantra Zoe , You Jia , Guo Qianjin , Zhang Hongbing , Sengupta Debrup , Boukhris Ahmad , Liu Cheng , Cresswell Peter , Dahia Patricia L. M. , Wang Jun , Aifantis Iannis 
Published: May 2023

Abstract
Acute Myeloid Leukemia (AML) is a clonal hematopoietic neoplasm, accounting for ~80% of acute leukemia cases in adults. The poor clinical outcome of AML patients (~27% five-year overall survival) is largely due to the inefficiency and toxicity of standard therapies. In the past decade, immunotherapies or cellular therapies (CAR-T/TCR-T cells) have achieved FDA approvals in certain types of solid tumors and leukemia, but currently there is no approved immunotherapy in AML. One potential reason is that AML actively inhibits antigen presentation (AP) to reduce its immunogenicity, thus dampening the efficacies of immunotherapies. This growing consensus is supported by the clinical evidence that AML exhibits low levels of AP machinery at diagnosis and even lower when relapsed from conventional chemotherapies. Besides, better outcomes could be achieved when combining immune checkpoint blockade with neo-antigens-inducing hypomethylating agents, highlighting the importance of AP in AML. We thus hypothesize that targeting tumor-endogenous AP suppressors will enhance AML immunogenicity and benefit immunotherapies.
Recent studies have suggested that autophagy or soluble protein PCSK9 can mediate MHC-I degradation or disrupt MHC-I recycling, respectively. Transcription/epigenetic repressors TRAF3 and EZH2, as well as thymidylate synthase, were identified as MHC-I inhibitors. However, their specificity in MHC-I modulation and precise roles in regulating tumor antigenic peptide-MHC-I complexes (pMHC-I) are still unclear. Hence, there is an increasing need to identify AML-specific AP regulation mechanisms.
To map such mechanisms, we performed pMHC-I-guided CRISPR screens in both human and mouse AML cell lines. Through these screens, we constructed positive and negative regulatory networks of pMHC-I modulation and compared the role of these novel regulators in the simultaneous modulation of MHC-I expression. This is the first-in-class systematic identification of AP regulators in AML. Among these negative AP regulators, we are particularly interested in the interferon regulatory factor 2 binding protein 2 (IRF2BP2), an AML-specific transcriptional regulator that is highly expressed in AML compared with normal hematopoietic stem and progenitor cells (HSPCs). Notably, IRF2BP2 expression negatively correlates with major histocompatibility complex class I (MHC-I) expression, interferon (IFN) response signatures, and T cell activity in AML patients. Ablation of IRF2BP2 enhanced AP in AML and facilitated T cell-mediated elimination of AML. Moreover, IRF2BP2 depletion synergized with IFN treatment to further boost AP at both transcriptional and protein levels. Our findings reveal a new class of tumor-associated immune-evasion mechanisms that target AP, with potential application as therapeutic targets for next-generation cancer immunotherapies.
Citation Format: Xufeng Chen, Qiao Lu, Hua Zhou, Jia Liu, Bettina Nadorp, Audrey Lasry, Zhengxi Sun, Jiangyan Zhang, Michael Cammer, Kun Wang, Zoe Ciantra, Jia You, Qianjin Guo, Hongbing Zhang, Debrup Sengupta, Ahmad Boukhris, Cheng Liu, Peter Cresswell, Patricia L. M. Dahia, Jun Wang, Iannis Aifantis. Targeting MHC-I antigen presentation for cancer immune evasion in acute myeloid leukemia [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A10.