Dong Zhang, Min Wang, Wenying Wang, Shiya Ma, Wenwen Yu, Xiubao Ren, Qian Sun
Triple-negative breast cancer is a high-risk form of breast cancer with a high metastatic potential and lack of effective therapies. Immunotherapy has shown encouraging clinical benefits, and its efficacy in triple-negative breast cancer is affected by immunocyte infiltration in the tumor microenvironment. PGAM1 is a key enzyme involved in cancer metabolism; however, its role in the tumor microenvironment remains unclear. In this study, we aimed to investigate the role of PGAM1 in triple-negative breast cancer and determine the potential of PGAM1 inhibition in combination with anti-PD-1 immunotherapy. Our results showed that PGAM1 is highly expressed in triple-negative breast cancer and is associated with poor prognosis. In vivo experiments demonstrated that PGAM1 inhibition synergizes with anti-PD-1 immunotherapy, significantly remodeling the tumor microenvironment and leading to an increase in antitumor immunocytes, such as CD8+ T cells and M1 macrophages, and a reduction in immunosuppressive cell infiltration, including myeloid-derived suppressor cells, M2 macrophages, and regulatory T cells. Functional and animal experiments showed that this synergistic mechanism inhibited tumor growth in vitro and in vivo. We identified PGAM1 as a novel target that exhibits an antitumor effect via the regulation of immunocyte infiltration. Our results show that PGAM1 can synergize with anti-PD-1 immunotherapy, providing a novel treatment strategy for triple-negative breast cancer.
{"title":"PGAM1 suppression remodels the tumor microenvironment in triple-negative breast cancer and synergizes with anti-PD-1 immunotherapy.","authors":"Dong Zhang, Min Wang, Wenying Wang, Shiya Ma, Wenwen Yu, Xiubao Ren, Qian Sun","doi":"10.1093/jleuko/qiae065","DOIUrl":"10.1093/jleuko/qiae065","url":null,"abstract":"<p><p>Triple-negative breast cancer is a high-risk form of breast cancer with a high metastatic potential and lack of effective therapies. Immunotherapy has shown encouraging clinical benefits, and its efficacy in triple-negative breast cancer is affected by immunocyte infiltration in the tumor microenvironment. PGAM1 is a key enzyme involved in cancer metabolism; however, its role in the tumor microenvironment remains unclear. In this study, we aimed to investigate the role of PGAM1 in triple-negative breast cancer and determine the potential of PGAM1 inhibition in combination with anti-PD-1 immunotherapy. Our results showed that PGAM1 is highly expressed in triple-negative breast cancer and is associated with poor prognosis. In vivo experiments demonstrated that PGAM1 inhibition synergizes with anti-PD-1 immunotherapy, significantly remodeling the tumor microenvironment and leading to an increase in antitumor immunocytes, such as CD8+ T cells and M1 macrophages, and a reduction in immunosuppressive cell infiltration, including myeloid-derived suppressor cells, M2 macrophages, and regulatory T cells. Functional and animal experiments showed that this synergistic mechanism inhibited tumor growth in vitro and in vivo. We identified PGAM1 as a novel target that exhibits an antitumor effect via the regulation of immunocyte infiltration. Our results show that PGAM1 can synergize with anti-PD-1 immunotherapy, providing a novel treatment strategy for triple-negative breast cancer.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140119802","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}
The mammalian immune system is constantly surveying our tissues to clear pathogens and maintain tissue homeostasis. In order to fulfill these tasks, immune cells take up nutrients to supply energy for survival and for directly regulating effector functions via their cellular metabolism, a process now known as immunometabolism. Neutrophilic granulocytes, the most abundant leukocytes in the human body, have a short half-life and are permanently needed in the defense against pathogens. According to a long-standing view, neutrophils were thought to primarily fuel their metabolic demands via glycolysis. Yet, this view has been challenged, as other metabolic pathways recently emerged to contribute to neutrophil homeostasis and effector functions. In particular during neutrophilic development, the pentose phosphate pathway, glycogen synthesis, oxidative phosphorylation, and fatty acid oxidation crucially promote neutrophil maturation. At steady state, both glucose and lipid metabolism sustain neutrophil survival and maintain the intracellular redox balance. This review aims to comprehensively discuss how neutrophilic metabolism adapts during development, which metabolic pathways fuel their functionality, and how these processes are reconfigured in case of various diseases. We provide several examples of hereditary diseases, in which mutations in metabolic enzymes validate their critical role for neutrophil function.
{"title":"Not just sugar: metabolic control of neutrophil development and effector functions.","authors":"Paul Ettel, Thomas Weichhart","doi":"10.1093/jleuko/qiae057","DOIUrl":"10.1093/jleuko/qiae057","url":null,"abstract":"<p><p>The mammalian immune system is constantly surveying our tissues to clear pathogens and maintain tissue homeostasis. In order to fulfill these tasks, immune cells take up nutrients to supply energy for survival and for directly regulating effector functions via their cellular metabolism, a process now known as immunometabolism. Neutrophilic granulocytes, the most abundant leukocytes in the human body, have a short half-life and are permanently needed in the defense against pathogens. According to a long-standing view, neutrophils were thought to primarily fuel their metabolic demands via glycolysis. Yet, this view has been challenged, as other metabolic pathways recently emerged to contribute to neutrophil homeostasis and effector functions. In particular during neutrophilic development, the pentose phosphate pathway, glycogen synthesis, oxidative phosphorylation, and fatty acid oxidation crucially promote neutrophil maturation. At steady state, both glucose and lipid metabolism sustain neutrophil survival and maintain the intracellular redox balance. This review aims to comprehensively discuss how neutrophilic metabolism adapts during development, which metabolic pathways fuel their functionality, and how these processes are reconfigured in case of various diseases. We provide several examples of hereditary diseases, in which mutations in metabolic enzymes validate their critical role for neutrophil function.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140049614","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}
In this study, we report on longitudinal kinetics of cellular immune subsets following SARS-CoV-2 infection in a cohort of hospitalized individuals and evaluate the interplay of these profiles with infecting viral variants, humoral immunity including neutralizing responses, vaccination history and clinical outcomes. A cohort of 121 SARS-CoV-2 infected individuals exhibiting varying disease states were prospectively evaluated for lymphopenic profiles, anti-viral humoral responses and infecting viral variants for a period of up to 90 days spanning the period, February 2021-January 2022 (2nd and 3rd waves of infection). A total of 51 participants received at least one vaccine dose of indigenous vaccines (Covishield or Covaxin) prior to recruitment. When stratified in terms of mortality, B and NK cells, in contrast to the T cell compartment, did not recover from nadir levels in non-survivors who were largely unvaccinated. No discriminatory signature was identified for non-survivors in terms of anti-NC or anti-S1-RBD IgG CLIA profiles including GenScript S1-RBD assays. Evaluation of sVCAM and sMAdCAM revealed opposing dynamics that correlated with disease severity and convalescence respectively. Viral variant analysis revealed delta and omicron variants to comprise majority of the infections which reflected national transmission kinetics during the period of recruitment. Our results demonstrate the importance of monitoring circulating biomarkers for convalescence as well as mortality in COVID-19 progression. Delta variants of SARS-CoV-2 clearly demonstrated increased pathogenicity and warrants sustained viral surveillance for re-emergence of these strains. Our findings with respect to vaccination advocate for continued vaccine development and administration of COVID-19 vaccines.
{"title":"Integrated viral and immune monitoring in a prospective COVID-19 cohort from India.","authors":"Sachee Agrawal, Nandini Kasarpalkar, Sayantani Ghosh, Gaurav Paradkar, Vaibhav Daund, Shilpa Bhowmick, Vidushi Chitalia, Priyanka Rao, Ashwini Sankpal, Varsha Kalsurkar, Karan Shah, Sameen Khan, Ashwini Patil, Dhanashree Jagtap, Omkar Khandkar, Mala Kaneria, Smita D Mahale, Geetanjali Sachdeva, Vikrant M Bhor, Jayanthi Shastri, Vainav Patel","doi":"10.1093/jleuko/qiae187","DOIUrl":"https://doi.org/10.1093/jleuko/qiae187","url":null,"abstract":"<p><p>In this study, we report on longitudinal kinetics of cellular immune subsets following SARS-CoV-2 infection in a cohort of hospitalized individuals and evaluate the interplay of these profiles with infecting viral variants, humoral immunity including neutralizing responses, vaccination history and clinical outcomes. A cohort of 121 SARS-CoV-2 infected individuals exhibiting varying disease states were prospectively evaluated for lymphopenic profiles, anti-viral humoral responses and infecting viral variants for a period of up to 90 days spanning the period, February 2021-January 2022 (2nd and 3rd waves of infection). A total of 51 participants received at least one vaccine dose of indigenous vaccines (Covishield or Covaxin) prior to recruitment. When stratified in terms of mortality, B and NK cells, in contrast to the T cell compartment, did not recover from nadir levels in non-survivors who were largely unvaccinated. No discriminatory signature was identified for non-survivors in terms of anti-NC or anti-S1-RBD IgG CLIA profiles including GenScript S1-RBD assays. Evaluation of sVCAM and sMAdCAM revealed opposing dynamics that correlated with disease severity and convalescence respectively. Viral variant analysis revealed delta and omicron variants to comprise majority of the infections which reflected national transmission kinetics during the period of recruitment. Our results demonstrate the importance of monitoring circulating biomarkers for convalescence as well as mortality in COVID-19 progression. Delta variants of SARS-CoV-2 clearly demonstrated increased pathogenicity and warrants sustained viral surveillance for re-emergence of these strains. Our findings with respect to vaccination advocate for continued vaccine development and administration of COVID-19 vaccines.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108190","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}
Kensuke Murata, Atsushi Murao, Chuyi Tan, Ping Wang, Monowar Aziz
B-1a cells, a regulatory subset of B lymphocytes, produce natural IgM and interleukin-10. Neutrophil extracellular traps (NETs) play a crucial role in pathogen defense, but their excessive formation during sepsis can cause further inflammation and tissue damage. In sepsis, extracellular cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, is released to induce NET formation. We hypothesize that B-1a cells clear NETs to prevent sepsis-induced injury. Sepsis in mice was induced by injecting 1 × 107 and 5 × 107 colony-forming units of Escherichia coli intraperitoneally. After 4 and 20 h, we assessed the number of B-1a cells in the peritoneal cavity using flow cytometry. Our results showed that the number of peritoneal B-1a cells was significantly decreased in E. coli sepsis mice. Importantly, replenishing B-1a cells via intraperitoneal injection in sepsis mice significantly decreased NETs in peritoneal neutrophils. We also observed a decrease in serum inflammation and injury markers and a significant increase in the overall survival rate in B-1a cell-treated septic mice. To understand the mechanism, we cocultured bone marrow-derived neutrophils with peritoneal B-1a cells in a contact or noncontact condition using an insert and stimulated them with eCIRP. After 4 h, we found that eCIRP significantly increased NET formation in bone marrow-derived neutrophils. Interestingly, we observed that B-1a cells inhibited NETs by 67% in a contact-dependent manner. Surprisingly, when B-1a cells were cultured in inserts, there was no significant decrease in NET formation, suggesting that direct cell-to-cell contact is crucial for this inhibitory effect. We further determined that B-1a cells promoted NET phagocytosis, and this was mediated through natural IgM, as blocking the IgM receptor attenuated the engulfment of NETs by B-1a cells. Finally, we identified that following their engulfment, NETs were localized into the lysosomal compartment for lysis. Thus, our study suggests that B-1a cells decrease NET content in eCIRP-treated neutrophils and E. coli sepsis mice.
{"title":"B-1a cells scavenge NETs to attenuate sepsis.","authors":"Kensuke Murata, Atsushi Murao, Chuyi Tan, Ping Wang, Monowar Aziz","doi":"10.1093/jleuko/qiae066","DOIUrl":"10.1093/jleuko/qiae066","url":null,"abstract":"<p><p>B-1a cells, a regulatory subset of B lymphocytes, produce natural IgM and interleukin-10. Neutrophil extracellular traps (NETs) play a crucial role in pathogen defense, but their excessive formation during sepsis can cause further inflammation and tissue damage. In sepsis, extracellular cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, is released to induce NET formation. We hypothesize that B-1a cells clear NETs to prevent sepsis-induced injury. Sepsis in mice was induced by injecting 1 × 107 and 5 × 107 colony-forming units of Escherichia coli intraperitoneally. After 4 and 20 h, we assessed the number of B-1a cells in the peritoneal cavity using flow cytometry. Our results showed that the number of peritoneal B-1a cells was significantly decreased in E. coli sepsis mice. Importantly, replenishing B-1a cells via intraperitoneal injection in sepsis mice significantly decreased NETs in peritoneal neutrophils. We also observed a decrease in serum inflammation and injury markers and a significant increase in the overall survival rate in B-1a cell-treated septic mice. To understand the mechanism, we cocultured bone marrow-derived neutrophils with peritoneal B-1a cells in a contact or noncontact condition using an insert and stimulated them with eCIRP. After 4 h, we found that eCIRP significantly increased NET formation in bone marrow-derived neutrophils. Interestingly, we observed that B-1a cells inhibited NETs by 67% in a contact-dependent manner. Surprisingly, when B-1a cells were cultured in inserts, there was no significant decrease in NET formation, suggesting that direct cell-to-cell contact is crucial for this inhibitory effect. We further determined that B-1a cells promoted NET phagocytosis, and this was mediated through natural IgM, as blocking the IgM receptor attenuated the engulfment of NETs by B-1a cells. Finally, we identified that following their engulfment, NETs were localized into the lysosomal compartment for lysis. Thus, our study suggests that B-1a cells decrease NET content in eCIRP-treated neutrophils and E. coli sepsis mice.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11367732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140131740","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}
Ying Ma, Xuesong Li, Jin Zhang, Xiangqin Zhao, Yi Lu, Guangcong Shen, Guowen Wang, Hong Liu, Jihui Hao
Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor response to all therapeutic modalities and dismal prognosis. The presence of tertiary lymphoid structures (TLSs) in various solid cancers is of crucial prognostic significance, highlighting the intricate interplay between the tumor microenvironment and immune cells aggregation. However, the extent to which TLSs and immune status affect PDAC prognosis remains incompletely understood. Here, we sought to unveil the unique properties of TLSs in PDAC by leveraging both single-cell and bulk transcriptomics, culminating in a risk model that predicts clinical outcomes. We used TLS scores based on a 12-gene (CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13) and 9-gene (PTGDS, RBP5, EIF1AY, CETP, SKAP1, LAT, CCR6, CD1D, and CD79B) signature, respectively, and examined their distribution in cell clusters of single-cell data from PDAC samples. The markers involved in these clusters were selected to develop a prognostic model using The Cancer Genome Atlas Program database as the training cohort and Gene Expression Omnibus database as the validation cohort. Further, we compared the immune infiltration, drug sensitivity, and enriched and differentially expressed genes between the high- and low-risk groups in our model. Therefore, we established a risk model that has significant implications for the prognostic assessment of PADC patients with remarkable differences in immune infiltration and chemosensitivity between the low- and high-risk groups. This paradigm established by TLS-related cell marker genes provides a prognostic prediction and a panel of novel therapeutic targets for exploring potential immunotherapy.
{"title":"Integrating tertiary lymphoid structure-associated genes into computational models to evaluate prognostication and immune infiltration in pancreatic cancer.","authors":"Ying Ma, Xuesong Li, Jin Zhang, Xiangqin Zhao, Yi Lu, Guangcong Shen, Guowen Wang, Hong Liu, Jihui Hao","doi":"10.1093/jleuko/qiae067","DOIUrl":"10.1093/jleuko/qiae067","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor response to all therapeutic modalities and dismal prognosis. The presence of tertiary lymphoid structures (TLSs) in various solid cancers is of crucial prognostic significance, highlighting the intricate interplay between the tumor microenvironment and immune cells aggregation. However, the extent to which TLSs and immune status affect PDAC prognosis remains incompletely understood. Here, we sought to unveil the unique properties of TLSs in PDAC by leveraging both single-cell and bulk transcriptomics, culminating in a risk model that predicts clinical outcomes. We used TLS scores based on a 12-gene (CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13) and 9-gene (PTGDS, RBP5, EIF1AY, CETP, SKAP1, LAT, CCR6, CD1D, and CD79B) signature, respectively, and examined their distribution in cell clusters of single-cell data from PDAC samples. The markers involved in these clusters were selected to develop a prognostic model using The Cancer Genome Atlas Program database as the training cohort and Gene Expression Omnibus database as the validation cohort. Further, we compared the immune infiltration, drug sensitivity, and enriched and differentially expressed genes between the high- and low-risk groups in our model. Therefore, we established a risk model that has significant implications for the prognostic assessment of PADC patients with remarkable differences in immune infiltration and chemosensitivity between the low- and high-risk groups. This paradigm established by TLS-related cell marker genes provides a prognostic prediction and a panel of novel therapeutic targets for exploring potential immunotherapy.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140131742","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}
Weijiao Du, Fan Yang, Zhenzhen Hui, Jiali Zhang, Meng Shen, Xiubao Ren, Feng Wei
This study aimed to examine the spatial distribution of immune cells by application of Gcross function in 170 patients with stage I to IIIA lung adenocarcinoma (LUAD) and explore its prognostic value. A total of 170 stage I to IIIA LUAD patients who underwent radical surgery were enrolled. Paraffinized tumor sections were collected for 2 panels of multicolor immunofluorescence staining (panel 1: CD4, CD8, FOXP3, CD69, CD39, CD73, and DAPI; panel 2: CD68, CD163, CD20, CD11c, PDL1, IDO, and DAPI). The immune cells were categorized as CD8+, CD4+ T helper cell (CD4Th), regulatory T cell, macrophage type 1 (M1), M2, dendritic cell (DC), and B cell. The immune cell numbers were enumerated, and the immune cell proximity score was calculated employing the Gcross function. The correlation between immune cell variables and disease-free survival (DFS) was explored through univariate Cox regression analyses. Factors with P < 0.05 were subjected to multivariate analyses. According to univariate Cox regression analyses, total PDL1+ and PDL1+ DC counts were negative factors (P = 0.003 and 0.031, respectively). CD4Th and IDO-DC counts were positive factors (P = 0.022 and 0.024, respectively). The proximity score (M1 to M2) was a positive factor for DFS (P = 0.032), and the proximity score (PDL1 + DC to M1) was a negative factor (P = 0.009) according to univariate Cox analyses. In multivariate analyses, stage (IIIA vs I + II) (hazard ratio [HR]: 1.77 [95% confidence interval (CI): 1.18-2.64], P = 0.006) and proximity score (PDL1 + DC to M1) (HR: 1.60 [95% CI: 1.07-2.37], P = 0.021) were independent negative factors and CD4Th counts (HR: 0.60 [95% CI: 0.40-0.90], P = 0.013) was an independent positive factor. Our study indicated that a higher level of tumor-infiltrating CD4Th cells predicted longer DFS, and a closer proximity of PDL1+ DCs to M1 cells was associated with dismal DFS in stage I to IIIA LUAD patients.
本研究旨在应用 Gcross 功能检测 170 例 I-IIIA 期肺腺癌(LUAD)患者体内免疫细胞的空间分布情况,并探讨其预后价值。该研究共纳入了170例接受根治性手术的I-IIIA期肺癌患者。采集石蜡切片进行以下两组多色免疫荧光染色:第 1 组(CD4、CD8、FOXP3、CD69、CD39、CD73 和 DAPI)和第 2 组(CD68、CD163、CD20、CD11c、PDL1、IDO 和 DAPI)。免疫细胞分为 CD8+、CD4+ T 辅助细胞(CD4Th)、调节性 T 细胞(Treg)、1 型巨噬细胞(M1)、2 型巨噬细胞(M2)、树突状细胞(DC)和 B 细胞。对免疫细胞数量进行了统计,并利用 Gcross 函数计算了免疫细胞接近度得分。通过单变量 Cox 回归分析探讨了免疫细胞变量与无病生存期(DFS)之间的相关性。P
{"title":"Examining the spatial distribution of tumor-infiltrating immune cells in patients with stage I to IIIA LUAD.","authors":"Weijiao Du, Fan Yang, Zhenzhen Hui, Jiali Zhang, Meng Shen, Xiubao Ren, Feng Wei","doi":"10.1093/jleuko/qiae012","DOIUrl":"10.1093/jleuko/qiae012","url":null,"abstract":"<p><p>This study aimed to examine the spatial distribution of immune cells by application of Gcross function in 170 patients with stage I to IIIA lung adenocarcinoma (LUAD) and explore its prognostic value. A total of 170 stage I to IIIA LUAD patients who underwent radical surgery were enrolled. Paraffinized tumor sections were collected for 2 panels of multicolor immunofluorescence staining (panel 1: CD4, CD8, FOXP3, CD69, CD39, CD73, and DAPI; panel 2: CD68, CD163, CD20, CD11c, PDL1, IDO, and DAPI). The immune cells were categorized as CD8+, CD4+ T helper cell (CD4Th), regulatory T cell, macrophage type 1 (M1), M2, dendritic cell (DC), and B cell. The immune cell numbers were enumerated, and the immune cell proximity score was calculated employing the Gcross function. The correlation between immune cell variables and disease-free survival (DFS) was explored through univariate Cox regression analyses. Factors with P < 0.05 were subjected to multivariate analyses. According to univariate Cox regression analyses, total PDL1+ and PDL1+ DC counts were negative factors (P = 0.003 and 0.031, respectively). CD4Th and IDO-DC counts were positive factors (P = 0.022 and 0.024, respectively). The proximity score (M1 to M2) was a positive factor for DFS (P = 0.032), and the proximity score (PDL1 + DC to M1) was a negative factor (P = 0.009) according to univariate Cox analyses. In multivariate analyses, stage (IIIA vs I + II) (hazard ratio [HR]: 1.77 [95% confidence interval (CI): 1.18-2.64], P = 0.006) and proximity score (PDL1 + DC to M1) (HR: 1.60 [95% CI: 1.07-2.37], P = 0.021) were independent negative factors and CD4Th counts (HR: 0.60 [95% CI: 0.40-0.90], P = 0.013) was an independent positive factor. Our study indicated that a higher level of tumor-infiltrating CD4Th cells predicted longer DFS, and a closer proximity of PDL1+ DCs to M1 cells was associated with dismal DFS in stage I to IIIA LUAD patients.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139485730","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}
Immunoglobulin A nephropathy is a complex autoimmune disease with various underlying causes and significant clinical heterogeneity. There are large individual differences in its development, and the etiology and pathogenesis are still poorly understood. While it is known that immunobiological factors play a significant role in the pathophysiology of immunoglobulin A nephropathy, the specific nature of these factors has yet to be fully elucidated. Numerous investigations have verified that CD4+ and CD8+ T lymphocytes are involved in the immunopathogenesis of immunoglobulin A nephropathy. Furthermore, certain data also point to γδT cells' involvement in the pathophysiology of immunoglobulin A nephropathy. By thoroughly examining the mechanisms of action of these T cells in the context of immunoglobulin A nephropathy, this review sheds light on the immunopathogenesis of the disease and its associated factors. The review is intended to provide reference value for the future research in this field and promising treatment clues for clinical patients.
免疫球蛋白 A 肾病(IgAN)是一种复杂的自身免疫性疾病,其病因多种多样,临床表现具有明显的异质性。该病的发病存在很大的个体差异,病因和发病机制至今仍不十分清楚。虽然已知免疫生物学因素在 IgAN 的病理生理学中起着重要作用,但这些因素的具体性质尚未完全阐明。大量研究已经证实,分化群 4+(CD4+)和 CD8+ T 淋巴细胞参与了 IgAN 的免疫发病机制。此外,某些数据还表明γδT 细胞参与了 IgAN 的病理生理学。通过深入研究这些 T 细胞在 IgAN 中的作用机制,本综述揭示了该疾病的免疫发病机制及其相关因素。本综述旨在为该领域的未来研究提供参考价值,并为临床患者提供有希望的治疗线索。
{"title":"T cell responses in immune-mediated IgA nephropathy.","authors":"Shimin Xie, Mengying Sun, Xiaohan Zhang, Chao Kan, Guojuan Shi, Weixiang Peng, Junli Guo, Dantong Wu, Zhinan Yin, Quanli Yang, Rui Zhang","doi":"10.1093/jleuko/qiae103","DOIUrl":"10.1093/jleuko/qiae103","url":null,"abstract":"<p><p>Immunoglobulin A nephropathy is a complex autoimmune disease with various underlying causes and significant clinical heterogeneity. There are large individual differences in its development, and the etiology and pathogenesis are still poorly understood. While it is known that immunobiological factors play a significant role in the pathophysiology of immunoglobulin A nephropathy, the specific nature of these factors has yet to be fully elucidated. Numerous investigations have verified that CD4+ and CD8+ T lymphocytes are involved in the immunopathogenesis of immunoglobulin A nephropathy. Furthermore, certain data also point to γδT cells' involvement in the pathophysiology of immunoglobulin A nephropathy. By thoroughly examining the mechanisms of action of these T cells in the context of immunoglobulin A nephropathy, this review sheds light on the immunopathogenesis of the disease and its associated factors. The review is intended to provide reference value for the future research in this field and promising treatment clues for clinical patients.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140861099","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}
Despite abundant evidence correlating T cell CD38 expression and HIV infection pathogenesis, its role as a CD4T cell immunometabolic regulator remains unclear. We find that CD38's extracellular glycohydrolase activity restricts metabolic reprogramming after T cell receptor (TCR)-engaging stimulation in Jurkat T CD4 cells, together with functional responses, while reducing intracellular nicotinamide adenine dinucleotide and nicotinamide mononucleotide concentrations. Selective elimination of CD38's ectoenzyme function licenses them to decrease the oxygen consumption rate/extracellular acidification rate ratio upon TCR signaling and to increase cycling, proliferation, survival, and CD40L induction. Pharmacological inhibition of ecto-CD38 catalytic activity in TM cells from chronic HIV-infected patients rescued TCR-triggered responses, including differentiation and effector functions, while reverting abnormally increased basal glycolysis, cycling, and spontaneous proinflammatory cytokine production. Additionally, ecto-CD38 blockage normalized basal and TCR-induced mitochondrial morphofunctionality, while increasing respiratory capacity in cells from HIV+ patients and healthy individuals. Ectoenzyme CD38's immunometabolic restriction of TCR-involving stimulation is relevant to CD4T cell biology and to the deleterious effects of CD38 overexpression in HIV disease.
尽管有大量证据表明 T 细胞 CD38 的表达与 HIV 感染的发病机制有关,但它作为 CD4 T 细胞免疫代谢调节因子的作用仍不清楚。我们发现,CD38 的细胞外糖化酶活性限制了 Jurkat T CD4 细胞在 TCR 结合刺激后的代谢重编程以及功能反应,同时降低了细胞内 NAD 和 NMN 的浓度。选择性消除 CD38 的外切酶功能可使它们在 TCR 信号转导后降低 OCR/ECAR 比率,并增加循环、增殖、存活和 CD40L 诱导。药理抑制慢性艾滋病病毒感染者记忆性 CD4 T 细胞中的外切 CD38 催化活性,可挽救 TCR 触发的反应,包括分化和效应功能,同时恢复异常增加的基础糖酵解、循环和自发性促炎细胞因子的产生。此外,阻断外切酶 CD38 可使基础线粒体形态和 TCR 诱导的线粒体功能正常化,同时提高 HIV+ 患者和健康人细胞的呼吸能力。外切酶CD38对TCR诱导刺激的免疫代谢限制与CD4 T细胞生物学以及CD38过表达在HIV疾病中的有害影响有关。
{"title":"The ecto-enzyme CD38 modulates CD4T cell immunometabolic responses and participates in HIV pathogenesis.","authors":"Fernando Díaz-Basilio, Moisés Vergara-Mendoza, Jessica Romero-Rodríguez, Sharik Hernández-Rizo, Alejandro Escobedo-Calvario, Luis-León Fuentes-Romero, Santiago Pérez-Patrigeon, Akio Murakami-Ogasawara, María Gomez-Palacio, Gustavo Reyes-Terán, Wei Jiang, Joel-Armando Vázquez-Pérez, Álvaro Marín-Hernández, Dámaris-Priscila Romero-Rodríguez, María-Concepción Gutiérrez-Ruiz, Mónica Viveros-Rogel, Enrique Espinosa","doi":"10.1093/jleuko/qiae060","DOIUrl":"10.1093/jleuko/qiae060","url":null,"abstract":"<p><p>Despite abundant evidence correlating T cell CD38 expression and HIV infection pathogenesis, its role as a CD4T cell immunometabolic regulator remains unclear. We find that CD38's extracellular glycohydrolase activity restricts metabolic reprogramming after T cell receptor (TCR)-engaging stimulation in Jurkat T CD4 cells, together with functional responses, while reducing intracellular nicotinamide adenine dinucleotide and nicotinamide mononucleotide concentrations. Selective elimination of CD38's ectoenzyme function licenses them to decrease the oxygen consumption rate/extracellular acidification rate ratio upon TCR signaling and to increase cycling, proliferation, survival, and CD40L induction. Pharmacological inhibition of ecto-CD38 catalytic activity in TM cells from chronic HIV-infected patients rescued TCR-triggered responses, including differentiation and effector functions, while reverting abnormally increased basal glycolysis, cycling, and spontaneous proinflammatory cytokine production. Additionally, ecto-CD38 blockage normalized basal and TCR-induced mitochondrial morphofunctionality, while increasing respiratory capacity in cells from HIV+ patients and healthy individuals. Ectoenzyme CD38's immunometabolic restriction of TCR-involving stimulation is relevant to CD4T cell biology and to the deleterious effects of CD38 overexpression in HIV disease.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140101736","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}
Although tumor cell-derived microparticles (MPs) vaccines have reportedly induced antitumor immune reactions for various cancers, the mechanism by which MPs derived from Hepa1-6 cells are taken up by dendritic cells (DCs) and provide the MPs antigens message to CD8+ T cells to exert their anti-hepatocellular carcinoma (HCC) effects remain unclear. Furthermore, the role of MPs in combination with the small-molecule drug MSI-1436, an inhibitor of protein tyrosine phosphatase 1B (PTP1B), in HCC has not yet been reported. In this study, protein mass spectrometry combined with cytology revealed that MPs are mainly taken up by DCs via the clathrin-mediated endocytosis and phagocytosis pathway and localized mainly in lysosomes. High concentration of tumor necrosis factor-α and interferon-γ was detected in CD8+ T cells stimulated with MPs-loaded DCs. Moreover, MPs combined with MSI-1436 further suppressed the proliferation of HCC cells in C57BL/6 tumor-bearing mice, which was closely correlated with CD4+/CD8+ T cells counts in peripheral blood, spleen, and the tumor microenvironment. Mechanistically, the combination of MPs and MSI-1436 exerts a more powerful anti-HCC effect, which may be related to the further inhibition of the expression of PTP1B. Overall, MPs combined with MSI-1436 exerted stronger antitumor effects than MPs or MSI-1436 alone. Therefore, the combination of MPs and MSI-1436 may be a promising means of treating HCC.
{"title":"Combination of microparticles vaccine with MSI-1436 exerts a strong immune response for hepatocellular carcinoma.","authors":"Zhao Zhan, Jiaqing Cheng, Fang Liu, Shili Tao, Ling Wang, Xiandong Lin, Yunbin Ye","doi":"10.1093/jleuko/qiae159","DOIUrl":"10.1093/jleuko/qiae159","url":null,"abstract":"<p><p>Although tumor cell-derived microparticles (MPs) vaccines have reportedly induced antitumor immune reactions for various cancers, the mechanism by which MPs derived from Hepa1-6 cells are taken up by dendritic cells (DCs) and provide the MPs antigens message to CD8+ T cells to exert their anti-hepatocellular carcinoma (HCC) effects remain unclear. Furthermore, the role of MPs in combination with the small-molecule drug MSI-1436, an inhibitor of protein tyrosine phosphatase 1B (PTP1B), in HCC has not yet been reported. In this study, protein mass spectrometry combined with cytology revealed that MPs are mainly taken up by DCs via the clathrin-mediated endocytosis and phagocytosis pathway and localized mainly in lysosomes. High concentration of tumor necrosis factor-α and interferon-γ was detected in CD8+ T cells stimulated with MPs-loaded DCs. Moreover, MPs combined with MSI-1436 further suppressed the proliferation of HCC cells in C57BL/6 tumor-bearing mice, which was closely correlated with CD4+/CD8+ T cells counts in peripheral blood, spleen, and the tumor microenvironment. Mechanistically, the combination of MPs and MSI-1436 exerts a more powerful anti-HCC effect, which may be related to the further inhibition of the expression of PTP1B. Overall, MPs combined with MSI-1436 exerted stronger antitumor effects than MPs or MSI-1436 alone. Therefore, the combination of MPs and MSI-1436 may be a promising means of treating HCC.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620177","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}