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Structural insights reveal interplay between LAG-3 homodimerization, ligand binding, and function

Silberstein, John L; Du, Jasper; Chan, Kun-Wei; Frank, Jessica A; Mathews, Irimpan I; Kim, Yong Bin; You, Jia; Lu, Qiao; Liu, Jia; Philips, Elliot A; Liu, Phillip; Rao, Eric; Fernandez, Daniel; Rodriguez, Grayson E; Kong, Xiang-Peng; Wang, Jun; Cochran, Jennifer R
Lymphocyte activation gene-3 (LAG-3) is an inhibitory receptor expressed on activated T cells and an emerging immunotherapy target. Domain 1 (D1) of LAG-3, which has been purported to directly interact with major histocompatibility complex class II (MHCII) and fibrinogen-like protein 1 (FGL1), has been the major focus for the development of therapeutic antibodies that inhibit LAG-3 receptor-ligand interactions and restore T cell function. Here, we present a high-resolution structure of glycosylated mouse LAG-3 ectodomain, identifying that cis-homodimerization, mediated through a network of hydrophobic residues within domain 2 (D2), is critically required for LAG-3 function. Additionally, we found a previously unidentified key protein-glycan interaction in the dimer interface that affects the spatial orientation of the neighboring D1 domain. Mutation of LAG-3 D2 residues reduced dimer formation, dramatically abolished LAG-3 binding to both MHCII and FGL1 ligands, and consequentially inhibited the role of LAG-3 in suppressing T cell responses. Intriguingly, we showed that antibodies directed against D1, D2, and D3 domains are all capable of blocking LAG-3 dimer formation and MHCII and FGL-1 ligand binding, suggesting a potential allosteric model of LAG-3 function tightly regulated by dimerization. Furthermore, our work reveals unique epitopes, in addition to D1, that can be targeted for immunotherapy of cancer and other human diseases.
PMCID:10962948
PMID: 38483996
ISSN: 1091-6490
CID: 5639842

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

PD-1H/VISTA mediates immune evasion in acute myeloid leukemia

Kim, Tae Kon; Han, Xue; Hu, Qianni; Vandsemb, Esten N; Fielder, Carly M; Hong, Junshik; Kim, Kwang Woon; Mason, Emily F; Plowman, R Skipper; Wang, Jun; Wang, Qi; Zhang, Jian-Ping; Badri, Ti; Sanmamed, Miguel F; Zheng, Linghua; Zhang, Tianxiang; Alawa, Jude; Lee, Sang Won; Zeidan, Amer M; Halene, Stephanie; Pillai, Manoj M; Chandhok, Namrata S; Lu, Jun; Xu, Mina L; Gore, Steven D; Chen, Lieping
Acute myeloid leukemia (AML) presents a pressing medical need in that it is largely resistant to standard chemotherapy as well as modern therapeutics such as targeted therapy and immunotherapy, including anti-PD therapy. We demonstrate that Programmed Death-1 Homolog (PD-1H), an immune co-inhibitory molecule is highly expressed in blasts from the bone marrow of AML patients, while normal myeloid cell subsets and T cells have the expression of PD-1H. In studies employing syngeneic and humanized AML mouse models, overexpression of PD-1H promoted the growth of AML cells, mainly by evading T cell-mediated immune responses. Importantly, ablation of AML cell surface PD-1H by antibody blockade or genetic targeting significantly inhibited AML progression by promoting T cell activity. In addition, the genetic deletion of PD-1H from host normal myeloid cells inhibited AML progression as well and the combination of PD-1H blockade with PD-1 blockade conferred a synergistic anti-leukemia effect. Our findings provide the basis for PD-1H as an attractive therapeutic target to treat human AML.
PMID: 38060328
ISSN: 1558-8238
CID: 5591322

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

CD137 (4-1BB)-Based Cancer Immunotherapy on Its 25th Anniversary

Melero, Ignacio; Sanmamed, Miguel F; Glez-Vaz, Javier; Luri-Rey, Carlos; Wang, Jun; Chen, Lieping
UNLABELLED:Twenty-five years ago, we reported that agonist anti-CD137 monoclonal antibodies eradicated transplanted mouse tumors because of enhanced CD8+ T-cell antitumor immunity. Mouse models indicated that anti-CD137 agonist antibodies synergized with various other therapies. In the clinic, the agonist antibody urelumab showed evidence for single-agent activity against melanoma and non-Hodgkin lymphoma but caused severe liver inflammation in a fraction of the patients. CD137's signaling domain is included in approved chimeric antigen receptors conferring persistence and efficacy. A new wave of CD137 agonists targeting tumors, mainly based on bispecific constructs, are in early-phase trials and are showing promising safety and clinical activity. SIGNIFICANCE:CD137 (4-1BB) is a costimulatory receptor of T and natural killer lymphocytes whose activity can be exploited in cancer immunotherapy strategies as discovered 25 years ago. Following initial attempts that met unacceptable toxicity, new waves of constructs acting agonistically on CD137 are being developed in patients, offering signs of clinical and pharmacodynamic activity with tolerable safety profiles.
PMID: 36576322
ISSN: 2159-8290
CID: 5447812

Social trauma engages lateral septum circuitry to occlude social reward

Li, Long; Durand-de Cuttoli, Romain; Aubry, Antonio V; Burnett, C Joseph; Cathomas, Flurin; Parise, Lyonna F; Chan, Kenny L; Morel, Carole; Yuan, Chongzhen; Shimo, Yusuke; Lin, Hsiao-Yun; Wang, Jun; Russo, Scott J
In humans, traumatic social experiences can contribute to psychiatric disorders1. It is suggested that social trauma impairs brain reward function such that social behaviour is no longer rewarding, leading to severe social avoidance2,3. In rodents, the chronic social defeat stress (CSDS) model has been used to understand the neurobiology underlying stress susceptibility versus resilience following social trauma, yet little is known regarding its impact on social reward4,5. Here we show that, following CSDS, a subset of male and female mice, termed susceptible (SUS), avoid social interaction with non-aggressive, same-sex juvenile C57BL/6J mice and do not develop context-dependent social reward following encounters with them. Non-social stressors have no effect on social reward in either sex. Next, using whole-brain Fos mapping, in vivo Ca2+ imaging and whole-cell recordings, we identified a population of stress/threat-responsive lateral septum neurotensin (NTLS) neurons that are activated by juvenile social interactions only in SUS mice, but not in resilient or unstressed control mice. Optogenetic or chemogenetic manipulation of NTLS neurons and their downstream connections modulates social interaction and social reward. Together, these data suggest that previously rewarding social targets are possibly perceived as social threats in SUS mice, resulting from hyperactive NTLS neurons that occlude social reward processing.
PMCID:9876792
PMID: 36450985
ISSN: 1476-4687
CID: 5414412

Regulation of autoimmune disease progression by Pik3ip1 through metabolic reprogramming in T cells and therapeutic implications

Xie, Wenqiang; Fang, Juan; Shan, Zhongyan; Guo, Junyi; Liao, Yuan; Zou, Zhaolei; Wang, Jun; Wen, Shuqiong; Yang, Lisa; Zhang, Yanshu; Lu, Huanzi; Zhao, Hang; Kuang, Dong-Ming; Huang, Peng; Chen, Qianming; Wang, Zhi
Metabolic alterations could profoundly affect immune functions and influence the progression and outcome of autoimmune diseases. However, the detailed mechanisms and their therapeutic potential remain to be defined. Here, we show that phosphatidylinositide 3-kinase interacting protein 1 (Pik3ip1), a newly identified negative immune regulator, is notably down-regulated in several major autoimmune diseases through a previously unidentified mechanism mediated by interleukin-21/p38 mitogen-activated protein kinase/a disintegrin and metalloprotease-17 (ADAM17) pathway. Down-regulation of Pik3ip1 in T cells causes a major metabolic shift from oxidative phosphorylation toward aerobic glycolysis, leading to their overactivation and aggressive disease progression in experimental autoimmune encephalomyelitis (EAE) mouse model. Suppression of hypoxia-inducible factor 1α (Hif1α) or pharmacologic inhibition of glycolysis could reverse these phenotypes and largely mitigate EAE severity. Our study reveals a previously unrecognized role of Pik3ip1 in metabolic regulation that substantially affects the inflammatory loop in the autoimmune setting and identifies the Pik3ip1/Hif1α/glycolysis axis as a potential therapeutic target for treatment of autoimmune diseases.
PMID: 36179018
ISSN: 2375-2548
CID: 5334652

PD-L1 crosslinking as a new strategy of 4-1BB agonism immunotherapy

Shu, Fei; Punekar, Salman R; Velcheti, Vamsidhar; Sanmamed, Miguel F; Wang, Jun
4-1BB has been considered a promising target in cancer immunotherapy for decades. Nevertheless, early 4-1BB-targeted agent demonstrated significant liver immuno-toxicity. A new wave of 4-1BB-based therapy is being developed to circumvent hepatotoxicity with bispecific molecule that directs 4-1BB agonism to the tumor microenvironment by targeting tumor-associated immune checkpoint molecule, PD-L1.
PMID: 35648093
ISSN: 1557-3265
CID: 5236062

Stereospecific Effects of Benzimidazolonepiperidine Compounds on T-Type Ca2+ Channels and Pain

Gomez, Kimberly; Tang, Cheng; Tan, Bin; Perez-Miller, Samantha; Ran, Dongzhi; Loya, Santiago; Calderon-Rivera, Aida; Stratton, Harrison J; Duran, Paz; Masterson, Kyleigh A; Gabrielsen, Anna T; Alsbiei, Omar; Dorame, Angie; Serafini, Maria; Moutal, Aubin; Wang, Jun; Khanna, Rajesh
T-type calcium channels activate in response to subthreshold membrane depolarizations and represent an important source of Ca2+ influx near the resting membrane potential. These channels regulate neuronal excitability and have been linked to pain. For this reason, T-type calcium channels are suitable molecular targets for the development of new non-opioid analgesics. Our previous work identified an analogue of benzimidazolonepiperidine, 5bk, that preferentially inhibited CaV3.2 channels and reversed mechanical allodynia. In this study, we synthesized and screened a small library of 47 compounds derived from 5bk. We found several compounds that inhibited the Ca2+ influx in DRG neurons of all sizes. After separating the enantiomers of each active compound, we found two compounds, 3-25-R and 3-14-3-S, that potently inhibited the Ca2+ influx. Whole-cell patch clamp recordings from small- to medium-sized DRG neurons revealed that both compounds decreased total Ca2+. Application of 3-14-3-S (but not 3-25-R) blocked transiently expressed CaV3.1-3.3 channels with a similar IC50 value. 3-14-3-S decreased T-type, but not N-type, Ca2+ currents in DRG neurons. Furthermore, intrathecal delivery of 3-14-3-S relieved tonic, neuropathic, and inflammatory pain in preclinical models. 3-14-3-S did not exhibit any activity against G protein-coupled opioid receptors. Preliminary docking studies also suggest that 3-14-3-S can bind to the central pore domain of T-type channels. Together, our chemical characterization and functional and behavioral data identify a novel T-type calcium channel blocker with in vivo efficacy in experimental models of tonic, neuropathic, and inflammatory pain.
PMID: 35671441
ISSN: 1948-7193
CID: 5249752

Platelets contribute to disease severity in COVID-19

Barrett, Tessa J; Bilaloglu, Seda; Cornwell, Macintosh; Burgess, Hannah M; Virginio, Vitor W; Drenkova, Kamelia; Ibrahim, Homam; Yuriditsky, Eugene; Aphinyanaphongs, Yin; Lifshitz, Mark; Xia Liang, Feng; Alejo, Julie; Smith, Grace; Pittaluga, Stefania; Rapkiewicz, Amy V; Wang, Jun; Iancu-Rubin, Camelia; Mohr, Ian; Ruggles, Kelly; Stapleford, Kenneth A; Hochman, Judith; Berger, Jeffrey S
OBJECTIVE:Heightened inflammation, dysregulated immunity, and thrombotic events are characteristic of hospitalized COVID-19 patients. Given that platelets are key regulators of thrombosis, inflammation, and immunity they represent prime candidates as mediators of COVID-19-associated pathogenesis. The objective of this study was to understand the contribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to the platelet phenotype via phenotypic (activation, aggregation) and transcriptomic characterization. APPROACH AND RESULTS/UNASSIGNED:In a cohort of 3915 hospitalized COVID-19 patients, we analyzed blood platelet indices collected at hospital admission. Following adjustment for demographics, clinical risk factors, medication, and biomarkers of inflammation and thrombosis, we find platelet count, size, and immaturity are associated with increased critical illness and all-cause mortality. Bone marrow, lung tissue, and blood from COVID-19 patients revealed the presence of SARS-CoV-2 virions in megakaryocytes and platelets. Characterization of COVID-19 platelets found them to be hyperreactive (increased aggregation, and expression of P-selectin and CD40) and to have a distinct transcriptomic profile characteristic of prothrombotic large and immature platelets. In vitro mechanistic studies highlight that the interaction of SARS-CoV-2 with megakaryocytes alters the platelet transcriptome, and its effects are distinct from the coronavirus responsible for the common cold (CoV-OC43). CONCLUSIONS:Platelet count, size, and maturity associate with increased critical illness and all-cause mortality among hospitalized COVID-19 patients. Profiling tissues and blood from COVID-19 patients revealed that SARS-CoV-2 virions enter megakaryocytes and platelets and associate with alterations to the platelet transcriptome and activation profile.
PMID: 34538015
ISSN: 1538-7836
CID: 5018172