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Targeting MHC-I inhibitory pathways for cancer immunotherapy

Wang, Jun; Lu, Qiao; Chen, Xufeng; Aifantis, Iannis
The MHC-I antigen presentation (AP) pathway is key to shaping mammalian CD8+ T cell immunity, with its aberrant expression closely linked to low tumor immunogenicity and immunotherapy resistance. While significant attention has been given to genetic mutations and downregulation of positive regulators that are essential for MHC-I AP, there is a growing interest in understanding how tumors actively evade MHC-I expression and/or AP through the induction of MHC-I inhibitory pathways. This emerging field of study may offer more viable therapeutic targets for future cancer immunotherapy. Here, we explore potential mechanisms by which cancer cells evade MHC-I AP and function and propose therapeutic strategies that might target these MHC-I inhibitors to restore impaired T cell immunity within the tumor microenvironment (TME).
PMID: 38433029
ISSN: 1471-4981
CID: 5639782

A membrane-associated MHC-I inhibitory axis for cancer immune evasion

Chen, Xufeng; Lu, Qiao; Zhou, Hua; Liu, Jia; Nadorp, Bettina; Lasry, Audrey; Sun, Zhengxi; Lai, Baoling; Rona, Gergely; Zhang, Jiangyan; Cammer, Michael; Wang, Kun; Al-Santli, Wafa; Ciantra, Zoe; Guo, Qianjin; You, Jia; Sengupta, Debrup; Boukhris, Ahmad; Zhang, Hongbing; Liu, Cheng; Cresswell, Peter; Dahia, Patricia L M; Pagano, Michele; Aifantis, Iannis; Wang, Jun
Immune-checkpoint blockade has revolutionized cancer treatment, but some cancers, such as acute myeloid leukemia (AML), do not respond or develop resistance. A potential mode of resistance is immune evasion of T cell immunity involving aberrant major histocompatibility complex class I (MHC-I) antigen presentation (AP). To map such mechanisms of resistance, we identified key MHC-I regulators using specific peptide-MHC-I-guided CRISPR-Cas9 screens in AML. The top-ranked negative regulators were surface protein sushi domain containing 6 (SUSD6), transmembrane protein 127 (TMEM127), and the E3 ubiquitin ligase WWP2. SUSD6 is abundantly expressed in AML and multiple solid cancers, and its ablation enhanced MHC-I AP and reduced tumor growth in a CD8+ T cell-dependent manner. Mechanistically, SUSD6 forms a trimolecular complex with TMEM127 and MHC-I, which recruits WWP2 for MHC-I ubiquitination and lysosomal degradation. Together with the SUSD6/TMEM127/WWP2 gene signature, which negatively correlates with cancer survival, our findings define a membrane-associated MHC-I inhibitory axis as a potential therapeutic target for both leukemia and solid cancers.
PMID: 37557169
ISSN: 1097-4172
CID: 5602312

Mitophagy promotes resistance to BH3 mimetics in acute myeloid leukemia

Glytsou, Christina; Chen, Xufeng; Zacharioudakis, Emmanouil; Al-Santli, Wafa; Zhou, Hua; Nadorp, Bettina; Lee, Soobeom; Lasry, Audrey; Sun, Zhengxi; Papaioannou, Dimitrios; Cammer, Michael; Wang, Kun; Zal, Tomasz; Zal, Malgorzata Anna; Carter, Bing Z; Ishizawa, Jo; Tibes, Raoul; Tsirigos, Aristotelis; Andreeff, Michael; Gavathiotis, Evripidis; Aifantis, Iannis
BH3-mimetics are used as an efficient strategy to induce cell death in several blood malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL-2 antagonist, is used clinically in combination with hypomethylating agents for the treatment of AML. Moreover, MCL-1 or dual BCL-2/BCL-xL antagonists are under investigation. Yet, resistance to single or combinatorial BH3-mimetics therapies eventually ensues. Integration of multiple genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy modulators sensitizes AML cells to various BH3-mimetics targeting different BCL-2 family members. One such regulator is MFN2, whose protein levels positively correlate with drug resistance in patients with AML. MFN2 overexpression is sufficient to drive resistance to BH3-mimetics in AML. Insensitivity to BH3-mimetics is accompanied by enhanced mitochondria-endoplasmic reticulum interactions and augmented mitophagy flux which acts as a pro-survival mechanism to eliminate mitochondrial damage. Genetic or pharmacologic MFN2 targeting synergizes with BH3-mimetics by impairing mitochondrial clearance and enhancing apoptosis in AML.
PMID: 37088914
ISSN: 2159-8290
CID: 5464912

Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion

Battistello, Elena; Hixon, Kimberlee A; Comstock, Dawn E; Collings, Clayton K; Chen, Xufeng; Rodriguez Hernaez, Javier; Lee, Soobeom; Cervantes, Kasey S; Hinkley, Madeline M; Ntatsoulis, Konstantinos; Cesarano, Annamaria; Hockemeyer, Kathryn; Haining, W Nicholas; Witkowski, Matthew T; Qi, Jun; Tsirigos, Aristotelis; Perna, Fabiana; Aifantis, Iannis; Kadoch, Cigall
Highly coordinated changes in gene expression underlie T cell activation and exhaustion. However, the mechanisms by which such programs are regulated and how these may be targeted for therapeutic benefit remain poorly understood. Here, we comprehensively profile the genomic occupancy of mSWI/SNF chromatin remodeling complexes throughout acute and chronic T cell stimulation, finding that stepwise changes in localization over transcription factor binding sites direct site-specific chromatin accessibility and gene activation leading to distinct phenotypes. Notably, perturbation of mSWI/SNF complexes using genetic and clinically relevant chemical strategies enhances the persistence of T cells with attenuated exhaustion hallmarks and increased memory features in vitro and in vivo. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T expansion and results in improved anti-tumor control in vivo. These findings reveal the central role of mSWI/SNF complexes in the coordination of T cell activation and exhaustion and nominate small-molecule-based strategies for the improvement of current immunotherapy protocols.
PMID: 36944333
ISSN: 1097-4164
CID: 5462792

SARS-CoV-2 exacerbates proinflammatory responses in myeloid cells through C-type lectin receptors and Tweety family member 2

Lu, Qiao; Liu, Jia; Zhao, Shuai; Gomez Castro, Maria Florencia; Laurent-Rolle, Maudry; Dong, Jianbo; Ran, Xiaojuan; Damani-Yokota, Payal; Tang, Hongzhen; Karakousi, Triantafyllia; Son, Juhee; Kaczmarek, Maria E; Zhang, Ze; Yeung, Stephen T; McCune, Broc T; Chen, Rita E; Tang, Fei; Ren, Xianwen; Chen, Xufeng; Hsu, Jack C C; Teplova, Marianna; Huang, Betty; Deng, Haijing; Long, Zhilin; Mudianto, Tenny; Jin, Shumin; Lin, Peng; Du, Jasper; Zang, Ruochen; Su, Tina Tianjiao; Herrera, Alberto; Zhou, Ming; Yan, Renhong; Cui, Jia; Zhu, James; Zhou, Qiang; Wang, Tao; Ma, Jianzhu; Koralov, Sergei B; Zhang, Zemin; Aifantis, Iannis; Segal, Leopoldo N; Diamond, Michael S; Khanna, Kamal M; Stapleford, Kenneth A; Cresswell, Peter; Liu, Yue; Ding, Siyuan; Xie, Qi; Wang, Jun
Despite mounting evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) engagement with immune cells, most express little, if any, of the canonical receptor of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2). Here, using a myeloid cell receptor-focused ectopic expression screen, we identified several C-type lectins (DC-SIGN, L-SIGN, LSECtin, ASGR1, and CLEC10A) and Tweety family member 2 (TTYH2) as glycan-dependent binding partners of the SARS-CoV-2 spike. Except for TTYH2, these molecules primarily interacted with spike via regions outside of the receptor-binding domain. Single-cell RNA sequencing analysis of pulmonary cells from individuals with coronavirus disease 2019 (COVID-19) indicated predominant expression of these molecules on myeloid cells. Although these receptors do not support active replication of SARS-CoV-2, their engagement with the virus induced robust proinflammatory responses in myeloid cells that correlated with COVID-19 severity. We also generated a bispecific anti-spike nanobody that not only blocked ACE2-mediated infection but also the myeloid receptor-mediated proinflammatory responses. Our findings suggest that SARS-CoV-2-myeloid receptor interactions promote immune hyperactivation, which represents potential targets for COVID-19 therapy.
PMID: 34048708
ISSN: 1097-4180
CID: 4888442

Surface antigen-guided CRISPR screens identify regulators of myeloid leukemia differentiation

Wang, Eric; Zhou, Hua; Nadorp, Bettina; Cayanan, Geraldine; Chen, Xufeng; Yeaton, Anna H; Nomikou, Sofia; Witkowski, Matthew T; Narang, Sonali; Kloetgen, Andreas; Thandapani, Palaniraja; Ravn-Boess, Niklas; Tsirigos, Aristotelis; Aifantis, Iannis
Lack of cellular differentiation is a hallmark of many human cancers, including acute myeloid leukemia (AML). Strategies to overcome such a differentiation blockade are an approach for treating AML. To identify targets for differentiation-based therapies, we applied an integrated cell surface-based CRISPR platform to assess genes involved in maintaining the undifferentiated state of leukemia cells. Here we identify the RNA-binding protein ZFP36L2 as a critical regulator of AML maintenance and differentiation. Mechanistically, ZFP36L2 interacts with the 3' untranslated region of key myeloid maturation genes, including the ZFP36 paralogs, to promote their mRNA degradation and suppress terminal myeloid cell differentiation. Genetic inhibition of ZFP36L2 restores the mRNA stability of these targeted transcripts and ultimately triggers myeloid differentiation in leukemia cells. Epigenome profiling of several individuals with primary AML revealed enhancer modules near ZFP36L2 that associated with distinct AML cell states, establishing a coordinated epigenetic and post-transcriptional mechanism that shapes leukemic differentiation.
PMID: 33450187
ISSN: 1875-9777
CID: 4747382

Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia

Kloetgen, Andreas; Thandapani, Palaniraja; Ntziachristos, Panagiotis; Ghebrechristos, Yohana; Nomikou, Sofia; Lazaris, Charalampos; Chen, Xufeng; Hu, Hai; Bakogianni, Sofia; Wang, Jingjing; Fu, Yi; Boccalatte, Francesco; Zhong, Hua; Paietta, Elisabeth; Trimarchi, Thomas; Zhu, Yixing; Van Vlierberghe, Pieter; Inghirami, Giorgio G; Lionnet, Timothee; Aifantis, Iannis; Tsirigos, Aristotelis
Differences in three-dimensional (3D) chromatin architecture can influence the integrity of topologically associating domains (TADs) and rewire specific enhancer-promoter interactions, impacting gene expression and leading to human disease. Here we investigate the 3D chromatin architecture in T cell acute lymphoblastic leukemia (T-ALL) by using primary human leukemia specimens and examine the dynamic responses of this architecture to pharmacological agents. Systematic integration of matched in situ Hi-C, RNA-seq and CTCF ChIP-seq datasets revealed widespread differences in intra-TAD chromatin interactions and TAD boundary insulation in T-ALL. Our studies identify and focus on a TAD 'fusion' event associated with absence of CTCF-mediated insulation, enabling direct interactions between the MYC promoter and a distal super-enhancer. Moreover, our data also demonstrate that small-molecule inhibitors targeting either oncogenic signal transduction or epigenetic regulation can alter specific 3D interactions found in leukemia. Overall, our study highlights the impact, complexity and dynamic nature of 3D chromatin architecture in human acute leukemia.
PMID: 32203470
ISSN: 1546-1718
CID: 4357602

Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML

DiNardo, Courtney D; Tiong, Ing Soo; Quaglieri, Anna; MacRaild, Sarah; Loghavi, Sanam; Brown, Fiona C; Thijssen, Rachel; Pomilio, Giovanna; Ivey, Adam; Salmon, Jessica; Glytsou, Christina; Fleming, Shaun Alan; Zhang, Qi; Ma, Helen; Patel, Keyur P; Kornblau, Steven M; Xu, Zhen; Chua, Chong Chyn; Chen, X; Blombery, Piers; Flensburg, Christoffer; Cummings, Nik; Aifantis, Iannis; Kantarjian, Hagop; Huang, David Ching Siang; Roberts, Andrew W; Majewski, Ian J; Konopleva, Marina; Wei, Andrew H
The BCL-2 inhibitor venetoclax combined with hypomethylating agents or low-dose cytarabine represents an important new therapy for older or unfit patients with acute myeloid leukemia (AML). We analyzed 81 patients receiving these venetoclax-based combinations to identify molecular correlates of durable remission, response followed by relapse (adaptive resistance) or refractory disease (primary resistance). High response rates and durable remissions were typically associated with NPM1 or IDH2 mutations (mut), with prolonged molecular remissions prevalent for NPM1mut. Primary and adaptive resistance to venetoclax-based combinations were most commonly characterized by acquisition or enrichment of clones activating signaling pathways such as FLT3 or RAS, or bi-allelically perturbing TP53. Single cell studies highlighted the polyclonal nature of intra-tumoral resistance mechanisms in some cases. Among cases that were primary refractory, we identified heterogeneous and sometimes divergent interval changes in leukemic clones within a single cycle of therapy, highlighting the dynamic and rapid occurrence of therapeutic selection in AML. In functional studies, FLT3-ITD gain or TP53 loss conferred cross-resistance to both venetoclax and cytotoxic-based therapies. Collectively, we highlight molecular determinants of outcome with clinical relevance to patients with AML receiving venetoclax-based combination therapies.
PMID: 31932844
ISSN: 1528-0020
CID: 4264322

Targeting mitochondrial structure sensitizes acute myeloid leukemia to Venetoclax treatment

Chen, Xufeng; Glytsou, Christina; Zhou, Hua; Narang, Sonali; Reyna, Denis E; Lopez, Andrea; Sakellaropoulos, Theodore; Gong, Yixiao; Kloetgen, Andreas; Yap, Yoon Sing; Wang, Eric; Gavathiotis, Evripidis; Tsirigos, Aristotelis; Tibes, Raoul; Aifantis, Iannis
The BCL-2 family plays important roles in acute myeloid leukemia (AML). Venetoclax, a selective BCL-2 inhibitor, has received FDA approval for the treatment of AML. However, drug resistance ensues after prolonged treatment, highlighting the need for a greater understanding of the underlying mechanisms. Using a genome-wide CRISPR/Cas9 screen in human AML, we identified genes whose inactivation sensitizes AML blasts to Venetoclax. Genes involved in mitochondrial organization and function were significantly depleted throughout our screen, including the mitochondrial chaperonin CLPB. We demonstrated that CLPB is upregulated in human AML, it is further induced upon acquisition of Venetoclax resistance and its ablation sensitizes AML to Venetoclax. Mechanistically, CLPB maintains the mitochondrial cristae structure via its interaction with the cristae-shaping protein OPA1, whereas its loss promotes apoptosis by inducing cristae remodeling and mitochondrial stress responses. Overall, our data suggest that targeting mitochondrial architecture may provide a promising approach to circumvent Venetoclax resistance.
PMID: 31048321
ISSN: 2159-8290
CID: 3854932

Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia

Wang, Eric; Lu, Sydney X; Pastore, Alessandro; Chen, Xufeng; Imig, Jochen; Chun-Wei Lee, Stanley; Hockemeyer, Kathryn; Ghebrechristos, Yohana E; Yoshimi, Akihide; Inoue, Daichi; Ki, Michelle; Cho, Hana; Bitner, Lillian; Kloetgen, Andreas; Lin, Kuan-Ting; Uehara, Taisuke; Owa, Takashi; Tibes, Raoul; Krainer, Adrian R; Abdel-Wahab, Omar; Aifantis, Iannis
RNA-binding proteins (RBPs) are essential modulators of transcription and translation frequently dysregulated in cancer. We systematically interrogated RBP dependencies in human cancers using a comprehensive CRISPR/Cas9 domain-focused screen targeting RNA-binding domains of 490 classical RBPs. This uncovered a network of physically interacting RBPs upregulated in acute myeloid leukemia (AML) and crucial for maintaining RNA splicing and AML survival. Genetic or pharmacologic targeting of one key member of this network, RBM39, repressed cassette exon inclusion and promoted intron retention within mRNAs encoding HOXA9 targets as well as in other RBPs preferentially required in AML. The effects of RBM39 loss on splicing further resulted in preferential lethality of spliceosomal mutant AML, providing a strategy for treatment of AML bearing RBP splicing mutations.
PMID: 30799057
ISSN: 1878-3686
CID: 3721572