IF 32.4 1区医学

Immunity Pub Date : 2024-11-21 DOI: 10.1016/j.immuni.2024.10.015

Siyu Sun, Eunae You, Jungeui Hong, David Hoyos, Isabella S. Del Priore, Kaloyan M. Tsanov, Om Mattagajasingh, Andrea Di Gioacchino, Sajid A. Marhon, Jonathan Chacon-Barahona, Hao Li, Hua Jiang, Samira Hozeifi, Omar Rosas-Bringas, Katherine H. Xu, Yuhui Song, Evan R. Lang, Alexandra S. Rojas, Linda T. Nieman, Bidish K. Patel, Benjamin D. Greenbaum

{"title":"Cancer cells restrict immunogenicity of retrotransposon expression via distinct mechanisms","authors":"Siyu Sun, Eunae You, Jungeui Hong, David Hoyos, Isabella S. Del Priore, Kaloyan M. Tsanov, Om Mattagajasingh, Andrea Di Gioacchino, Sajid A. Marhon, Jonathan Chacon-Barahona, Hao Li, Hua Jiang, Samira Hozeifi, Omar Rosas-Bringas, Katherine H. Xu, Yuhui Song, Evan R. Lang, Alexandra S. Rojas, Linda T. Nieman, Bidish K. Patel, Benjamin D. Greenbaum","doi":"10.1016/j.immuni.2024.10.015","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.10.015","url":null,"abstract":"To thrive, cancer cells must navigate acute inflammatory signaling accompanying oncogenic transformation, such as via overexpression of repeat elements. We examined the relationship between immunostimulatory repeat expression, tumor evolution, and the tumor-immune microenvironment. Integration of multimodal data from a cohort of pancreatic ductal adenocarcinoma (PDAC) patients revealed expression of specific Alu repeats predicted to form double-stranded RNAs (dsRNAs) and trigger retinoic-acid-inducible gene I (RIG-I)-like-receptor (RLR)-associated type-I interferon (IFN) signaling. Such Alu-derived dsRNAs also anti-correlated with pro-tumorigenic macrophage infiltration in late stage tumors. We defined two complementary pathways whereby PDAC may adapt to such anti-tumorigenic signaling. In mutant TP53 tumors, ORF1p from long interspersed nuclear element (LINE)-1 preferentially binds Alus and decreases their expression, whereas adenosine deaminases acting on RNA 1 (ADAR1) editing primarily reduces dsRNA formation in wild-type TP53 tumors. Depletion of either LINE-1 ORF1p or ADAR1 reduced tumor growth in vitro. The fact that tumors utilize multiple pathways to mitigate immunostimulatory repeats implies the stress from their expression is a fundamental phenomenon to which PDAC, and likely other tumors, adapt.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"192 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A pan-family screen of nuclear receptors in immunocytes reveals ligand-dependent inflammasome control 免疫细胞核受体泛家族筛选揭示配体依赖性炎症小体控制

IF 32.4 1区医学

Immunity Pub Date : 2024-11-20 DOI: 10.1016/j.immuni.2024.10.010

Yutao Wang, Yanbo Zhang, Kyungsub Kim, Jichang Han, Daniel Okin, Zhaozhao Jiang, Liang Yang, Arum Subramaniam, Terry K. Means, Frank O. Nestlé, Katherine A. Fitzgerald, Gwendalyn J. Randolph, Cammie F. Lesser, Jonathan C. Kagan, Diane Mathis, Christophe Benoist

{"title":"A pan-family screen of nuclear receptors in immunocytes reveals ligand-dependent inflammasome control","authors":"Yutao Wang, Yanbo Zhang, Kyungsub Kim, Jichang Han, Daniel Okin, Zhaozhao Jiang, Liang Yang, Arum Subramaniam, Terry K. Means, Frank O. Nestlé, Katherine A. Fitzgerald, Gwendalyn J. Randolph, Cammie F. Lesser, Jonathan C. Kagan, Diane Mathis, Christophe Benoist","doi":"10.1016/j.immuni.2024.10.010","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.10.010","url":null,"abstract":"Ligand-dependent transcription factors of the nuclear receptor (NR) family regulate diverse aspects of metazoan biology, enabling communications between distant organs via small lipophilic molecules. Here, we examined the impact of each of 35 NRs on differentiation and homeostatic maintenance of all major immunological cell types in vivo through a “Rainbow-CRISPR” screen. Receptors for retinoic acid exerted the most frequent cell-specific roles. NR requirements varied for resident macrophages of different tissues. Deletion of either Rxra or Rarg reduced frequencies of GATA6+ large peritoneal macrophages (LPMs). Retinoid X receptor alpha (RXRα) functioned conventionally by orchestrating LPM differentiation through chromatin and transcriptional regulation, whereas retinoic acid receptor gamma (RARγ) controlled LPM survival by regulating pyroptosis via association with the inflammasome adaptor ASC. RARγ antagonists activated caspases, and RARγ agonists inhibited cell death induced by several inflammasome activators. Our findings provide a broad view of NR function in the immune system and reveal a noncanonical role for a retinoid receptor in modulating inflammasome pathways.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"53 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Acute suppression of mitochondrial ATP production prevents apoptosis and provides an essential signal for NLRP3 inflammasome activation 急性抑制线粒体 ATP 的产生可防止细胞凋亡，并为 NLRP3 炎症小体的激活提供重要信号

IF 32.4 1区医学

Immunity Pub Date : 2024-11-20 DOI: 10.1016/j.immuni.2024.10.012

Benedikt S. Saller, Svenja Wöhrle, Larissa Fischer, Clara Dufossez, Isabella L. Ingerl, Susanne Kessler, Maria Mateo-Tortola, Oliver Gorka, Felix Lange, Yurong Cheng, Emilia Neuwirt, Adinarayana Marada, Christoph Koentges, Chiara Urban, Philipp Aktories, Peter Reuther, Sebastian Giese, Susanne Kirschnek, Carolin Mayer, Johannes Pilic, Olaf Groß

{"title":"Acute suppression of mitochondrial ATP production prevents apoptosis and provides an essential signal for NLRP3 inflammasome activation","authors":"Benedikt S. Saller, Svenja Wöhrle, Larissa Fischer, Clara Dufossez, Isabella L. Ingerl, Susanne Kessler, Maria Mateo-Tortola, Oliver Gorka, Felix Lange, Yurong Cheng, Emilia Neuwirt, Adinarayana Marada, Christoph Koentges, Chiara Urban, Philipp Aktories, Peter Reuther, Sebastian Giese, Susanne Kirschnek, Carolin Mayer, Johannes Pilic, Olaf Groß","doi":"10.1016/j.immuni.2024.10.012","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.10.012","url":null,"abstract":"How mitochondria reconcile roles in functionally divergent cell death pathways of apoptosis and NLRP3 inflammasome-mediated pyroptosis remains elusive, as is their precise role in NLRP3 activation and the evolutionarily conserved physiological function of NLRP3. Here, we have shown that when cells were challenged simultaneously, apoptosis was inhibited and NLRP3 activation prevailed. Apoptosis inhibition by structurally diverse NLRP3 activators, including nigericin, imiquimod, extracellular ATP, particles, and viruses, was not a consequence of inflammasome activation but rather of their effects on mitochondria. NLRP3 activators turned out as oxidative phosphorylation (OXPHOS) inhibitors, which we found to disrupt mitochondrial cristae architecture, leading to trapping of cytochrome c. Although this effect was alone not sufficient for NLRP3 activation, OXPHOS inhibitors became triggers of NLRP3 when combined with resiquimod or Yoda-1, suggesting that NLRP3 activation requires two simultaneous cellular signals, one of mitochondrial origin. Therefore, OXPHOS and apoptosis inhibition by NLRP3 activators provide stringency in cell death decisions.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"178 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting the aminopeptidase ERAP enhances antitumor immunity by disrupting the NKG2A-HLA-E inhibitory checkpoint 以氨基肽酶 ERAP 为靶点，通过破坏 NKG2A-HLA-E 抑制检查点增强抗肿瘤免疫力

IF 32.4 1区医学

Immunity Pub Date : 2024-11-18 DOI: 10.1016/j.immuni.2024.10.013

Hsiao-Wei Tsao, Seth Anderson, Kenneth J. Finn, Jonathan J. Perera, Lomax F. Pass, Emily M. Schneider, Aiping Jiang, Rachel Fetterman, Cun Lan Chuong, Kaiya Kozuma, Marcia M. Stickler, Marc Creixell, Susan Klaeger, Kshiti Meera Phulphagar, Suzanna Rachimi, Eva K. Verzani, Niclas Olsson, Juan Dubrot, Matthew F. Pech, Whitney Silkworth, Robert T. Manguso

{"title":"Targeting the aminopeptidase ERAP enhances antitumor immunity by disrupting the NKG2A-HLA-E inhibitory checkpoint","authors":"Hsiao-Wei Tsao, Seth Anderson, Kenneth J. Finn, Jonathan J. Perera, Lomax F. Pass, Emily M. Schneider, Aiping Jiang, Rachel Fetterman, Cun Lan Chuong, Kaiya Kozuma, Marcia M. Stickler, Marc Creixell, Susan Klaeger, Kshiti Meera Phulphagar, Suzanna Rachimi, Eva K. Verzani, Niclas Olsson, Juan Dubrot, Matthew F. Pech, Whitney Silkworth, Robert T. Manguso","doi":"10.1016/j.immuni.2024.10.013","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.10.013","url":null,"abstract":"The aminopeptidase, endoplasmic reticulum aminopeptidase 1 (ERAP1), trims peptides for loading into major histocompatibility complex class I (MHC class I), and loss of this activity has broad effects on the MHC class I peptidome. Here, we investigated the impact of targeting ERAP1 in immune checkpoint blockade (ICB), as MHC class I interactions mediate both activating and inhibitory functions in antitumor immunity. Loss of ERAP sensitized mouse tumor models to ICB, and this sensitivity depended on CD8+ T cells and natural killer (NK) cells. In vivo suppression screens revealed that Erap1 deletion inactivated the inhibitory NKG2A-HLA-E checkpoint, which requires presentation of a restricted set of invariant epitopes (VL9) on HLA-E. Loss of ERAP altered the HLA-E peptidome, preventing NKG2A engagement. In humans, ERAP1 and ERAP2 showed functional redundancy for the processing and presentation of VL9, and loss of both inactivated the NKG2A checkpoint in cancer cells. Thus, loss of ERAP phenocopies the inhibition of the NKG2A-HLA-E pathway and represents an attractive approach to inhibit this critical checkpoint.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"99 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CAR T cells in autoimmune disease: On the road to remission 自身免疫性疾病中的 CAR T 细胞：通往缓解之路

IF 32.4 1区医学

Immunity Pub Date : 2024-11-15 DOI: 10.1016/j.immuni.2024.10.011

Georg Schett, Carl H. June

引用次数: 0

Sialylated IgG induces the transcription factor REST in alveolar macrophages to protect against lung inflammation and severe influenza disease Sialylated IgG 可诱导肺泡巨噬细胞中的转录因子 REST，从而防止肺部炎症和严重流感疾病的发生

IF 32.4 1区医学

Immunity Pub Date : 2024-11-13 DOI: 10.1016/j.immuni.2024.10.002

Saborni Chakraborty, Bowie Yik-Ling Cheng, Desmond L. Edwards, Joseph C. Gonzalez, David Kung-Chun Chiu, Hong Zheng, Courtney Scallan, Xinrong Guo, Gene S. Tan, Greg P. Coffey, Pamela B. Conley, Patrick S. Hume, William J. Janssen, Derek E. Byers, Philip A. Mudd, Jeffery Taubenberger, Matthew Memoli, Mark M. Davis, Katrin F. Chua, Michael S. Diamond, Taia T. Wang

{"title":"Sialylated IgG induces the transcription factor REST in alveolar macrophages to protect against lung inflammation and severe influenza disease","authors":"Saborni Chakraborty, Bowie Yik-Ling Cheng, Desmond L. Edwards, Joseph C. Gonzalez, David Kung-Chun Chiu, Hong Zheng, Courtney Scallan, Xinrong Guo, Gene S. Tan, Greg P. Coffey, Pamela B. Conley, Patrick S. Hume, William J. Janssen, Derek E. Byers, Philip A. Mudd, Jeffery Taubenberger, Matthew Memoli, Mark M. Davis, Katrin F. Chua, Michael S. Diamond, Taia T. Wang","doi":"10.1016/j.immuni.2024.10.002","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.10.002","url":null,"abstract":"While most respiratory viral infections resolve with little harm to the host, severe symptoms arise when infection triggers an aberrant inflammatory response that damages lung tissue. Host regulators of virally induced lung inflammation have not been well defined. Here, we show that enrichment for sialylated, but not asialylated immunoglobulin G (IgG), predicted mild influenza disease in humans and was broadly protective against heterologous influenza viruses in a murine challenge model. Mechanistic studies show that sialylated IgG mediated this protection by inducing the transcription factor repressor element-1 silencing transcription factor (REST), which repressed nuclear factor κB (NF-κB)-driven responses, preventing severe lung inflammation and protecting lung function during influenza infection. Therapeutic administration of a recombinant, sialylated Fc molecule in clinical development similarly activated REST and protected against severe influenza disease, demonstrating that this pathway could be clinically harnessed. Overall, induction of REST through sialylated IgG signaling is a strategy to limit inflammatory disease sequelae in infections caused by antigenically distinct influenza strains.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"3 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mx1-ing it up—Mitochondrial relay for interferon-dependent, unconventional IL-1β release in SLE monocytes Mx1-ing it up--系统性红斑狼疮单核细胞中干扰素依赖性、非常规 IL-1β 释放的线粒体继电器

IF 32.4 1区医学

Immunity Pub Date : 2024-11-12 DOI: 10.1016/j.immuni.2024.10.005

Andrea Dorfleutner, Christian Stehlik, Caroline A. Jefferies

引用次数: 0

Home at last: Mixed signals guide memory T cells to residency 终于回家了混合信号引导记忆 T 细胞前往居住地

IF 32.4 1区医学

Immunity Pub Date : 2024-11-12 DOI: 10.1016/j.immuni.2024.10.008

Kalle Liimatta, Elina I. Zúñiga

引用次数: 0

TKI resistance in brain metastasis: A CTLA4 state of mind 脑转移中的 TKI 抗药性：CTLA4 状态