In this study, antibody response and a single-cell RNA-seq analysis were conducted on peripheral blood mononuclear cells from five different groups: naïve subjects vaccinated with AZD1222 (AZ) or Ad5-nCoV (Cso), individuals previously infected and later vaccinated (hybrid) with AZD1222 (AZ-hb) or Ad5-nCoV (Cso-hb), and those who were infected and had recovered from COVID-19 (Inf). The results showed that AZ induced more robust neutralizing antibody responses than Cso. The single-cell RNA data revealed a high frequency of memory B cells in the Cso and Cso-hb. In contrast, AZ and AZ-hb groups exhibited the highest proportion of activated naïve B cells expressing CXCR4. Transcriptomic analysis of CD4+ and CD8+ T cells demonstrated a heterogeneous response following vaccination, hybrid immunity, or natural infection. However, a single dose of Ad5-nCoV was sufficient to strongly activate CD4+ T cells (naïve and memory) expressing ANX1 and FOS, similar to the hybrid response observed with AZ. An interesting finding was the robust activation of a subset of CD8+ T cells expressing GZMB, GZMH, and IFNG genes in the Cso-hb group. Our findings suggest that both vaccines effectively stimulated the cellular immune response; however, the Ad5-nCoV induced a more robust CD8+ T-cell response in previously infected individuals.
本研究对五组不同人群的外周血单核细胞进行了抗体反应和单细胞RNA-seq分析，这五组人群分别是：接种AZD1222（AZ）或Ad5-nCoV（Cso）疫苗的天真受试者、曾感染AZD1222（AZ-hb）或Ad5-nCoV（Cso-hb）并随后接种（混合）疫苗的受试者，以及曾感染COVID-19并已康复的受试者（Inf）。结果显示，AZ诱导的中和抗体反应比Cso更强。单细胞 RNA 数据显示，Cso 和 Cso-hb 中记忆 B 细胞的频率很高。相比之下，AZ和AZ-hb组中表达CXCR4的活化幼稚B细胞比例最高。对 CD4+ 和 CD8+ T 细胞的转录组分析表明，接种疫苗、混合免疫或自然感染后会产生不同的反应。然而，单剂量的Ad5-nCoV足以强烈激活表达ANX1和FOS的CD4+ T细胞（幼稚和记忆），这与AZ观察到的混合反应类似。一个有趣的发现是，Cso-hb 组中表达 GZMB、GZMH 和 IFNG 基因的 CD8+ T 细胞亚群被强力激活。我们的研究结果表明，两种疫苗都能有效刺激细胞免疫反应；但是，Ad5-nCoV能在先前感染的个体中诱导出更强的CD8+ T细胞反应。
{"title":"Comparative single-cell transcriptomic profile of hybrid immunity induced by adenovirus vector-based COVID-19 vaccines","authors":"Melissa García-Vega, Hui Wan, Mónica Reséndiz-Sandoval, Diana Hinojosa-Trujillo, Olivia Valenzuela, Verónica Mata-Haro, Freddy Dehesa-Canseco, Mario Solís-Hernández, Harold Marcotte, Qiang Pan-Hammarström, Jesús Hernández","doi":"10.1038/s41435-024-00270-x","DOIUrl":"10.1038/s41435-024-00270-x","url":null,"abstract":"In this study, antibody response and a single-cell RNA-seq analysis were conducted on peripheral blood mononuclear cells from five different groups: naïve subjects vaccinated with AZD1222 (AZ) or Ad5-nCoV (Cso), individuals previously infected and later vaccinated (hybrid) with AZD1222 (AZ-hb) or Ad5-nCoV (Cso-hb), and those who were infected and had recovered from COVID-19 (Inf). The results showed that AZ induced more robust neutralizing antibody responses than Cso. The single-cell RNA data revealed a high frequency of memory B cells in the Cso and Cso-hb. In contrast, AZ and AZ-hb groups exhibited the highest proportion of activated naïve B cells expressing CXCR4. Transcriptomic analysis of CD4+ and CD8+ T cells demonstrated a heterogeneous response following vaccination, hybrid immunity, or natural infection. However, a single dose of Ad5-nCoV was sufficient to strongly activate CD4+ T cells (naïve and memory) expressing ANX1 and FOS, similar to the hybrid response observed with AZ. An interesting finding was the robust activation of a subset of CD8+ T cells expressing GZMB, GZMH, and IFNG genes in the Cso-hb group. Our findings suggest that both vaccines effectively stimulated the cellular immune response; however, the Ad5-nCoV induced a more robust CD8+ T-cell response in previously infected individuals.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 2","pages":"158-167"},"PeriodicalIF":5.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140559882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-19DOI: 10.1038/s41435-024-00261-y
A. Guffroy, L. Jacquel, Y. Seeleuthner, N. Paul, V. Poindron, F. Maurier, V. Delannoy, A. C. Voegeli, P. Zhang, B. Nespola, A. Molitor, M. J. Apithy, P. Soulas-Sprauel, T. Martin, R. E. Voll, S. Bahram, V. Gies, J. L. Casanova, A. Cobat, B. Boisson, R. Carapito, A. S. Korganow
{"title":"Correction: An immunogenomic exome landscape of triple positive primary antiphospholipid patients","authors":"A. Guffroy, L. Jacquel, Y. Seeleuthner, N. Paul, V. Poindron, F. Maurier, V. Delannoy, A. C. Voegeli, P. Zhang, B. Nespola, A. Molitor, M. J. Apithy, P. Soulas-Sprauel, T. Martin, R. E. Voll, S. Bahram, V. Gies, J. L. Casanova, A. Cobat, B. Boisson, R. Carapito, A. S. Korganow","doi":"10.1038/s41435-024-00261-y","DOIUrl":"10.1038/s41435-024-00261-y","url":null,"abstract":"","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 2","pages":"176-176"},"PeriodicalIF":5.0,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41435-024-00261-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140174237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-18DOI: 10.1038/s41435-024-00268-5
Wu Yue, Zhou Huiling, Liu Yuxin, Wang Ling, Gao Feng, Liu Qicai
Repeated implantation failure (RIF) is one of the most prominent problems in the field of assisted reproduction. Neu5Gc on the surface of decidual macrophages (dMΦ) leads to different activation patterns of dMΦ, which affects embryo implantation and development. Cmah−/− (Neu5Gc-deficient) mice induced to produce anti-Neu5Gc antibodies in vivo were given a special diet rich in Neu5Gc and their fertility was monitored. The long-term diet rich in Neu5Gc induced the decrease of endometrial receptivity of female mice. The pregnancy rate of female mice fed the normal diet was 63.6% (n = 11) and the average number of embryos was 9.571 ± 1.272, while the pregnancy rate of female mice fed the diet rich in Neu5Gc was 36.4% (n = 11) and the average number of embryos in pregnant mice was 5.750 ± 3.304. The intake of Neu5Gc and the production of anti-Neu5Gc antibody led to M1 polarization of endometrial dMΦ and abnormal embryo implantation.
{"title":"Neu5Gc regulates decidual macrophages leading to abnormal embryo implantation","authors":"Wu Yue, Zhou Huiling, Liu Yuxin, Wang Ling, Gao Feng, Liu Qicai","doi":"10.1038/s41435-024-00268-5","DOIUrl":"10.1038/s41435-024-00268-5","url":null,"abstract":"Repeated implantation failure (RIF) is one of the most prominent problems in the field of assisted reproduction. Neu5Gc on the surface of decidual macrophages (dMΦ) leads to different activation patterns of dMΦ, which affects embryo implantation and development. Cmah−/− (Neu5Gc-deficient) mice induced to produce anti-Neu5Gc antibodies in vivo were given a special diet rich in Neu5Gc and their fertility was monitored. The long-term diet rich in Neu5Gc induced the decrease of endometrial receptivity of female mice. The pregnancy rate of female mice fed the normal diet was 63.6% (n = 11) and the average number of embryos was 9.571 ± 1.272, while the pregnancy rate of female mice fed the diet rich in Neu5Gc was 36.4% (n = 11) and the average number of embryos in pregnant mice was 5.750 ± 3.304. The intake of Neu5Gc and the production of anti-Neu5Gc antibody led to M1 polarization of endometrial dMΦ and abnormal embryo implantation.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 2","pages":"149-157"},"PeriodicalIF":5.0,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140157954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-13DOI: 10.1038/s41435-024-00264-9
Lionel Apetoh
While chemotherapeutic agents were long solely associated with immunosuppression, clinical data demonstrate that the combination of some chemotherapies with immunomodulators can be beneficial against cancer. Defining combinations featuring optimal anticancer activity along with minimal toxicity remains however a major challenge. Clinical evidence suggests that immune responses in patients treated with combination therapies are associated with progression-free survival. Progress in understanding the mechanisms responsible for anticancer immune responses following chemotherapy administration facilitated the translation of relevant chemoimmunotherapy combinations in the clinic.
{"title":"Chemoimmunotherapy combinations: translating basic knowledge into clinical successes","authors":"Lionel Apetoh","doi":"10.1038/s41435-024-00264-9","DOIUrl":"10.1038/s41435-024-00264-9","url":null,"abstract":"While chemotherapeutic agents were long solely associated with immunosuppression, clinical data demonstrate that the combination of some chemotherapies with immunomodulators can be beneficial against cancer. Defining combinations featuring optimal anticancer activity along with minimal toxicity remains however a major challenge. Clinical evidence suggests that immune responses in patients treated with combination therapies are associated with progression-free survival. Progress in understanding the mechanisms responsible for anticancer immune responses following chemotherapy administration facilitated the translation of relevant chemoimmunotherapy combinations in the clinic.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 2","pages":"99-101"},"PeriodicalIF":5.0,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41435-024-00264-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140119293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-12DOI: 10.1038/s41435-024-00265-8
Xinhui Li, Shan Liu, Laibin Zou, Min Dai, Chaobei Zhu
Multiple transcript isoforms of genes can be formed by processing and modifying the 5′ and 3′ ends of RNA. Herein, the aim of this study is to uncover the characteristics of RNA processing modification (RPM) in hepatocellular carcinoma (HCC), and to identify novel biomarkers and potential targets for treatment. Firstly, integrated bioinformatics analysis was carried out to identify risk prognostic RPM regulators (RPMRs). Then, we used these RPMRs to identify subtypes of HCC and explore differences in immune microenvironment and cellular function improvement pathways between the sub-types. Finally, we used the principal component analysis algorithms to estimate RPMscore, which were applied to 5 cohorts. Lower RPMscore among patients correlated with a declined survival rate, increased immune infiltration, and raised expression of immune checkpoints, aligning with the “immunity tidal model theory”. The RPMscore exhibited robust, which was validated in multiple datasets. Mechanistically, low RPMscore can create an immunosuppressive microenvironment in HCC by manipulating tumor-associated macrophages. Preclinically, patients with high RPMscore might benefit from immunotherapy. The RPMscore is helpful in clustering HCC patients with distinct prognosis and immunotherapy. Our RPMscore model can help clinicians to select personalized therapy for HCC patients, and RPMscore may act a part in the development of HCC.
{"title":"RNA processing modification mediated subtypes illustrate the distinctive features of tumor microenvironment in hepatocellular carcinoma","authors":"Xinhui Li, Shan Liu, Laibin Zou, Min Dai, Chaobei Zhu","doi":"10.1038/s41435-024-00265-8","DOIUrl":"10.1038/s41435-024-00265-8","url":null,"abstract":"Multiple transcript isoforms of genes can be formed by processing and modifying the 5′ and 3′ ends of RNA. Herein, the aim of this study is to uncover the characteristics of RNA processing modification (RPM) in hepatocellular carcinoma (HCC), and to identify novel biomarkers and potential targets for treatment. Firstly, integrated bioinformatics analysis was carried out to identify risk prognostic RPM regulators (RPMRs). Then, we used these RPMRs to identify subtypes of HCC and explore differences in immune microenvironment and cellular function improvement pathways between the sub-types. Finally, we used the principal component analysis algorithms to estimate RPMscore, which were applied to 5 cohorts. Lower RPMscore among patients correlated with a declined survival rate, increased immune infiltration, and raised expression of immune checkpoints, aligning with the “immunity tidal model theory”. The RPMscore exhibited robust, which was validated in multiple datasets. Mechanistically, low RPMscore can create an immunosuppressive microenvironment in HCC by manipulating tumor-associated macrophages. Preclinically, patients with high RPMscore might benefit from immunotherapy. The RPMscore is helpful in clustering HCC patients with distinct prognosis and immunotherapy. Our RPMscore model can help clinicians to select personalized therapy for HCC patients, and RPMscore may act a part in the development of HCC.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 2","pages":"132-148"},"PeriodicalIF":5.0,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140109760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-12DOI: 10.1038/s41435-024-00263-w
José María García-Aznar, Sara Alonso Alvarez, Teresa Bernal del Castillo
The transcription factor BCL11B plays an essential role in the development of central nervous system and T cell differentiation by regulating the expression of numerous genes involved in several pathways. Monoallelic defects in the BCL11B gene leading to loss-of-function are associated with a wide spectrum of phenotypes, including neurological disorders with or without immunological features and susceptibility to hematological malignancies. From the genetic point of view, the landscape of BCL11B mutations reported so far does not fully explain the genotype-phenotype correlation. In this review, we sought to compile the phenotypic and genotypic variables associated with previously reported mutations in this gene in order to provide a better understanding of the consequences of deleterious variants. We also highlight the importance of a careful evaluation of the mutation type, its location and the pattern of inheritance of the variants in order to assign the most accurate pathogenicity and actionability of the genetic findings.
转录因子 BCL11B 在中枢神经系统发育和 T 细胞分化过程中起着至关重要的作用，它调控着参与多种途径的众多基因的表达。BCL11B 基因的单倍性缺陷导致的功能缺失与多种表型有关，包括伴有或不伴有免疫学特征的神经系统疾病以及对血液恶性肿瘤的易感性。从遗传学的角度来看，迄今所报道的 BCL11B 基因突变情况并不能完全解释基因型与表型之间的相关性。在这篇综述中，我们试图梳理与之前报道的该基因突变相关的表型和基因型变量，以便更好地了解有害变异的后果。我们还强调了仔细评估变异类型、变异位置和变异遗传模式的重要性，以便最准确地确定遗传结果的致病性和可操作性。
{"title":"Pivotal role of BCL11B in the immune, hematopoietic and nervous systems: a review of the BCL11B-associated phenotypes from the genetic perspective","authors":"José María García-Aznar, Sara Alonso Alvarez, Teresa Bernal del Castillo","doi":"10.1038/s41435-024-00263-w","DOIUrl":"10.1038/s41435-024-00263-w","url":null,"abstract":"The transcription factor BCL11B plays an essential role in the development of central nervous system and T cell differentiation by regulating the expression of numerous genes involved in several pathways. Monoallelic defects in the BCL11B gene leading to loss-of-function are associated with a wide spectrum of phenotypes, including neurological disorders with or without immunological features and susceptibility to hematological malignancies. From the genetic point of view, the landscape of BCL11B mutations reported so far does not fully explain the genotype-phenotype correlation. In this review, we sought to compile the phenotypic and genotypic variables associated with previously reported mutations in this gene in order to provide a better understanding of the consequences of deleterious variants. We also highlight the importance of a careful evaluation of the mutation type, its location and the pattern of inheritance of the variants in order to assign the most accurate pathogenicity and actionability of the genetic findings.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 3","pages":"232-241"},"PeriodicalIF":5.0,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41435-024-00263-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140109759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-09DOI: 10.1038/s41435-024-00267-6
Ignacio Melero, Carmen Molina, Cristina Eguizabal, Maite Alvarez
{"title":"Intratumoral NK cell delivery combined with neutralization of the NKG2A pathway as treatment for solid cancer","authors":"Ignacio Melero, Carmen Molina, Cristina Eguizabal, Maite Alvarez","doi":"10.1038/s41435-024-00267-6","DOIUrl":"10.1038/s41435-024-00267-6","url":null,"abstract":"","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 5","pages":"437-439"},"PeriodicalIF":5.0,"publicationDate":"2024-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140068331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-08DOI: 10.1038/s41435-024-00266-7
Teresa Neuwirth, Azuah L. Gonzalez, Emilie Fisher-Gupta, Georg Stary
{"title":"Getting under the skin: resident memory CD8+ T cells have a second residence in the draining lymph node","authors":"Teresa Neuwirth, Azuah L. Gonzalez, Emilie Fisher-Gupta, Georg Stary","doi":"10.1038/s41435-024-00266-7","DOIUrl":"10.1038/s41435-024-00266-7","url":null,"abstract":"","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 2","pages":"105-107"},"PeriodicalIF":5.0,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41435-024-00266-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140065125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-23DOI: 10.1038/s41435-024-00260-z
Marisa Flook, Elena Rojano, Alvaro Gallego-Martinez, Alba Escalera-Balsera, Patricia Perez-Carpena, M. del Carmen Moleon, Rocio Gonzalez-Aguado, Victoria Rivero de Jesus, Emilio Domínguez-Durán, Lidia Frejo, Juan A. G. Ranea, Jose Antonio Lopez-Escamez
Meniere Disease (MD) is a chronic inner ear disorder characterized by vertigo attacks, sensorineural hearing loss, tinnitus, and aural fullness. Extensive evidence supporting the inflammatory etiology of MD has been found, therefore, by using transcriptome analysis, we aim to describe the inflammatory variants of MD. We performed Bulk RNAseq on 45 patients with definite MD and 15 healthy controls. MD patients were classified according to their basal levels of IL-1β into 2 groups: high and low. Differentially expression analysis was performed using the ExpHunter Suite, and cell type proportion was evaluated using the estimation algorithms xCell, ABIS, and CIBERSORTx. MD patients showed 15 differentially expressed genes (DEG) compared to controls. The top DEGs include IGHG1 (p = 1.64 $$times$$ 10−6) and IGLV3-21 (p = 6.28 $$times$$ 10−3), supporting a role in the adaptative immune response. Cytokine profiling defines a subgroup of patients with high levels of IL-1β with up-regulation of IL6 (p = 7.65 $$times$$ 10−8) and INHBA (p = 3.39 $$times$$ 10−7) genes. Transcriptomic data from peripheral blood mononuclear cells support a proinflammatory subgroup of MD patients with high levels of IL6 and an increase in naïve B-cells, and memory CD8+ T cells.
{"title":"Cytokine profiling and transcriptomics in mononuclear cells define immune variants in Meniere Disease","authors":"Marisa Flook, Elena Rojano, Alvaro Gallego-Martinez, Alba Escalera-Balsera, Patricia Perez-Carpena, M. del Carmen Moleon, Rocio Gonzalez-Aguado, Victoria Rivero de Jesus, Emilio Domínguez-Durán, Lidia Frejo, Juan A. G. Ranea, Jose Antonio Lopez-Escamez","doi":"10.1038/s41435-024-00260-z","DOIUrl":"10.1038/s41435-024-00260-z","url":null,"abstract":"Meniere Disease (MD) is a chronic inner ear disorder characterized by vertigo attacks, sensorineural hearing loss, tinnitus, and aural fullness. Extensive evidence supporting the inflammatory etiology of MD has been found, therefore, by using transcriptome analysis, we aim to describe the inflammatory variants of MD. We performed Bulk RNAseq on 45 patients with definite MD and 15 healthy controls. MD patients were classified according to their basal levels of IL-1β into 2 groups: high and low. Differentially expression analysis was performed using the ExpHunter Suite, and cell type proportion was evaluated using the estimation algorithms xCell, ABIS, and CIBERSORTx. MD patients showed 15 differentially expressed genes (DEG) compared to controls. The top DEGs include IGHG1 (p = 1.64 $$times$$ 10−6) and IGLV3-21 (p = 6.28 $$times$$ 10−3), supporting a role in the adaptative immune response. Cytokine profiling defines a subgroup of patients with high levels of IL-1β with up-regulation of IL6 (p = 7.65 $$times$$ 10−8) and INHBA (p = 3.39 $$times$$ 10−7) genes. Transcriptomic data from peripheral blood mononuclear cells support a proinflammatory subgroup of MD patients with high levels of IL6 and an increase in naïve B-cells, and memory CD8+ T cells.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 2","pages":"124-131"},"PeriodicalIF":5.0,"publicationDate":"2024-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41435-024-00260-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139939907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-22DOI: 10.1038/s41435-024-00262-x
Michael Saitakis
Limited CAR T-cell expansion and persistence hinder therapeutic responses in solid cancer patients. To enhance the functional persistence of engineered T-cell therapies, we performed genetic disruption in human CAR T cells of SUV39H1, a histone 3 lysine 9 methyltransferase that promotes heterochromatin formation. This resulted in phenotypic CAR-T reprogramming that elicited optimal and sustained antitumor functionality. Single-cell transcriptomic (scRNA-seq) and chromatin accessibility (scATAC-seq) analyses of tumor-infiltrating CAR T cells showed early reprogramming into self-renewing, stem-like populations with decreased expression of dysfunction genes in all subpopulations. Moreover, we provided evidence that SUV39H1 inactivation elicits potent and durable functional persistence upon multiple tumor rechallenges. This opens a safe path to enhancing adoptive cell therapies for solid tumors.
有限的 CAR T 细胞扩增和持久性阻碍了实体瘤患者的治疗反应。为了提高工程 T 细胞疗法的功能持久性，我们在人类 CAR T 细胞中对 SUV39H1 进行了基因干扰，SUV39H1 是组蛋白 3 赖氨酸 9 甲基转移酶，能促进异染色质的形成。这导致了表型 CAR-T 重编程，从而激发了最佳和持续的抗肿瘤功能。对肿瘤浸润CAR-T细胞进行的单细胞转录组（scRNA-seq）和染色质可及性（scATAC-seq）分析表明，CAR-T细胞早期重编程为自我更新的干样细胞群，所有亚群中功能障碍基因的表达均有所下降。此外，我们还提供了证据表明，SUV39H1 失活可在多次肿瘤再挑战后产生强大而持久的功能持续性。这为加强实体瘤的采纳细胞疗法开辟了一条安全之路。
{"title":"Epigenetic reprogramming of CAR T cells for in vivo functional persistence against solid tumors","authors":"Michael Saitakis","doi":"10.1038/s41435-024-00262-x","DOIUrl":"10.1038/s41435-024-00262-x","url":null,"abstract":"Limited CAR T-cell expansion and persistence hinder therapeutic responses in solid cancer patients. To enhance the functional persistence of engineered T-cell therapies, we performed genetic disruption in human CAR T cells of SUV39H1, a histone 3 lysine 9 methyltransferase that promotes heterochromatin formation. This resulted in phenotypic CAR-T reprogramming that elicited optimal and sustained antitumor functionality. Single-cell transcriptomic (scRNA-seq) and chromatin accessibility (scATAC-seq) analyses of tumor-infiltrating CAR T cells showed early reprogramming into self-renewing, stem-like populations with decreased expression of dysfunction genes in all subpopulations. Moreover, we provided evidence that SUV39H1 inactivation elicits potent and durable functional persistence upon multiple tumor rechallenges. This opens a safe path to enhancing adoptive cell therapies for solid tumors.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 5","pages":"434-436"},"PeriodicalIF":5.0,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139930837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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