Immunology最新文献

{"title":"Aspergillus fumigatus-derived gliotoxin impacts innate immune cell activation through modulating lipid mediator production in macrophages","authors":"Kerstin Günther,&nbsp;Vivien Nischang,&nbsp;Zoltan Cseresnyés,&nbsp;Thomas Krüger,&nbsp;Dalia Sheta,&nbsp;Zahraa Abboud,&nbsp;Thorsten Heinekamp,&nbsp;Markus Werner,&nbsp;Olaf Kniemeyer,&nbsp;Andreas Beilhack,&nbsp;Marc Thilo Figge,&nbsp;Axel A. Brakhage,&nbsp;Oliver Werz,&nbsp;Paul M. Jordan","doi":"10.1111/imm.13857","DOIUrl":"10.1111/imm.13857","url":null,"abstract":"<p>Gliotoxin (GT), a secondary metabolite and virulence factor of the fungal pathogen <i>Aspergillus fumigatus</i>, suppresses innate immunity and supports the suppression of host immune responses. Recently, we revealed that GT blocks the formation of the chemotactic lipid mediator leukotriene (LT)B₄ in activated human neutrophils and monocytes, and in rodents <i>in vivo,</i> by directly inhibiting LTA₄ hydrolase. Here, we elucidated the impact of GT on LTB₄ biosynthesis and the entire lipid mediator networks in human M1- and M2-like monocyte-derived macrophages (MDMs) and in human tissue-resident alveolar macrophages. In activated M1-MDMs with high capacities to generate LTs, the formation of LTB₄ was effectively suppressed by GT, connected to attenuated macrophage phagocytic activity as well as human neutrophil movement and migration. In resting macrophages, especially in M1-MDMs, GT elicited strong formation of prostaglandins, while bacterial exotoxins from <i>Staphylococcus aureus</i> evoked a broad spectrum of lipid mediator biosynthesis in both MDM phenotypes. We conclude that GT impairs functions of activated innate immune cells through selective suppression of LTB₄ biosynthesis, while GT may also prime the immune system by provoking prostaglandin formation in macrophages.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"173 4","pages":"748-767"},"PeriodicalIF":4.9,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imm.13857","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142261863","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}

{"title":"Featured Cover","authors":"","doi":"10.1111/imm.13862","DOIUrl":"https://doi.org/10.1111/imm.13862","url":null,"abstract":"<p>Cover illustration: The cover image is based on the article <i>Erythropoietin induces tumour progression and CD39 expression on immune cells in a preclinical model of triple-negative breast cancer</i> by Stéphanie Bessoles et al., https://doi.org/10.1111/imm.13832.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"173 2","pages":"i"},"PeriodicalIF":4.9,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imm.13862","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174227","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}

{"title":"Inherent metabolic preferences differentially regulate the sensitivity of Th1 and Th2 cells to ribosome-inhibiting antibiotics","authors":"Neha Jawla,&nbsp;Raunak Kar,&nbsp;Veena S. Patil,&nbsp;G. Aneeshkumar Arimbasseri","doi":"10.1111/imm.13860","DOIUrl":"10.1111/imm.13860","url":null,"abstract":"<p>Mitochondrial translation is essential to maintain mitochondrial function and energy production. Mutations in genes associated with mitochondrial translation cause several developmental disorders, and immune dysfunction is observed in many such patients. Besides genetic mutations, several antibiotics targeting bacterial ribosomes are well-established to inhibit mitochondrial translation. However, the effect of such antibiotics on different immune cells is not fully understood. Here, we addressed the differential effect of mitochondrial translation inhibition on different subsets of helper T cells (Th) of mice and humans. Inhibition of mitochondrial translation reduced the levels of mitochondrially encoded electron transport chain subunits without affecting their nuclear-encoded counterparts. As a result, mitochondrial oxygen consumption reduced dramatically, but mitochondrial mass was unaffected. Most importantly, we show that inhibition of mitochondrial translation induced apoptosis, specifically in Th2 cells. This increase in apoptosis was associated with higher expression of Bim and Puma, two activators of the intrinsic pathway of apoptosis. We propose that this difference in the sensitivity of Th1 and Th2 cells to mitochondrial translation inhibition reflects the intrinsic metabolic demands of these subtypes. Though Th1 and Th2 cells exhibit similar levels of oxidative phosphorylation, Th1 cells exhibit higher levels of aerobic glycolysis than Th2 cells. Moreover, Th1 cells are more sensitive to the inhibition of glycolysis, while higher concentrations of glycolysis inhibitor 2-deoxyglucose are required to induce cell death in the Th2 lineage. These observations reveal that selection of metabolic pathways for substrate utilization during differentiation of Th1 and Th2 lineages is a fundamental process conserved across species.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"174 1","pages":"73-91"},"PeriodicalIF":4.9,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142214522","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}

{"title":"Identification of psoriasis-associated immune marker G3BP2 through single-cell RNA sequencing and meta analysis","authors":"Shuangshuang Gao,&nbsp;Huayu Fan,&nbsp;Ting Wang,&nbsp;Jinguang Chen","doi":"10.1111/imm.13851","DOIUrl":"10.1111/imm.13851","url":null,"abstract":"<p>Psoriasis is a chronic skin disease with an increasing prevalence each year. However, the mechanisms underlying its onset and progression remain unclear, and effective therapeutic targets are lacking. Therefore, we employs an innovative approach by combining single-cell RNA sequencing (scRNA-seq) with meta-analysis. This not only elucidates the potential mechanisms of psoriasis at the cellular level but also identifies immunoregulatory marker genes that play a statistically significant role in driving psoriasis progression through comprehensive analysis of multiple datasets. Skin tissue samples from 12 psoriasis patients underwent scRNA-seq, followed by quality control, filtering, PCA dimensionality reduction, and tSNE clustering analysis to identify T cell subtypes and differentially expressed genes (DEGs) in psoriatic skin tissue. Next, three psoriasis datasets were standardised and merged to identify differentially expressed genes (DEGs). Subsequently, weighted gene co-expression network analysis (WGCNA) was applied for clustering analysis of gene co-expression network modules and to assess the correlation between these modules and DEGs. Least absolute shrinkage and selection operator (LASSO) regression and receiver operating characteristic (ROC) curve analyses were conducted to select disease-specific genes and evaluate their diagnostic value. Single-cell data revealed nine cell types in psoriatic skin tissue, with seven T cell subtypes identified. Intersection analysis identified ADAM8 and G3BP2 as key genes. Through the integration of scRNA-seq and Meta analysis, we identified the immunoregulatory marker gene G3BP2, which is associated with the onset and progression of psoriasis and holds clinical significance. G3BP2 is speculated to promote the development of psoriasis by increasing the proportion of CD8+ T cells.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"173 4","pages":"730-747"},"PeriodicalIF":4.9,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142261865","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}

{"title":"CCR5-mediated homing of regulatory T cells and monocytic-myeloid derived suppressor cells to dysfunctional endothelium contributes to early atherosclerosis","authors":"Shamima Akhtar,&nbsp;Komal Sagar,&nbsp;Ambuj Roy,&nbsp;Milind P. Hote,&nbsp;Sudheer Arava,&nbsp;Alpana Sharma","doi":"10.1111/imm.13859","DOIUrl":"10.1111/imm.13859","url":null,"abstract":"<p>A disbalance between immune regulatory cells and inflammatory cells is known to drive atherosclerosis. However, the exact mechanism is not clear. Here, we investigated the homing of immune regulatory cells, mainly, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) subsets in asymptomatic coronary artery disease (CAD) risk factor-exposed young individuals (dyslipidemia [DLP] group) and stable CAD patients (CAD group). Compared with healthy controls (HCs), Tregs frequency was reduced in both DLP and CAD groups but expressed high levels of CCR5 in both groups. The frequency of monocytic-myeloid-derived suppressor cells (M-MDSCs) was increased while polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were decreased in CAD patients only. Interestingly, although unchanged in frequency, M-MDSCs of the DLP group expressed high levels of CCR5. Serum levels of chemokines (CCL5, CX3CL1, CCL26) and inflammatory cytokines (IL-6, IL-1β, IFN-γ, TNF-α) were higher in the DLP group. Stimulation with inflammatory cytokines augmented CCR5 expression in Tregs and M-MDSCs isolated from HCs. Activated endothelial cells showed elevated levels of CX3CL1 and CCL5 in vitro. Blocking CCR5 with D-Ala-peptide T-amide (DAPTA) increased Treg and M-MDSC frequency in C57Bl6 mice fed a high-fat diet. In accelerated atherosclerosis model, DAPTA treatment led to the formation of smooth muscle-rich plaque with less macrophages. Thus, we show that CCR5-CCL5 axis is instrumental in recruiting Tregs and M-MDSCs to dysfunctional endothelium in the asymptomatic phase of atherosclerosis contributing to atherosclerosis progression. Drugs targeting CCR5 in asymptomatic and CAD risk-factor/s-exposed individuals might be a novel therapeutic regime to diminish atherogenesis.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"173 4","pages":"712-729"},"PeriodicalIF":4.9,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142214523","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}

{"title":"Contributions of each of the BAFF receptors to the lymphocyte profiles in C57BL/6 mice","authors":"William Stohl,&nbsp;Ying Wu,&nbsp;Malka Stohl","doi":"10.1111/imm.13856","DOIUrl":"10.1111/imm.13856","url":null,"abstract":"<p>BAFF, a vital B cell survival and differentiation factor, has three receptors: B-cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) and BR3. Although B cells are greatly reduced in B6.<i>Baff</i>^−/− (which harbour no BAFF) and B6.<i>Br3</i>^−/− mice (which harbour supra-normal levels of BAFF), the distributions of B cell subsets and relationships between Foxp3⁺ and CD4⁺ cells in these mice differ. Using a large panel of B6 congenic knockout and/or transgenic mice, we demonstrate that (1) supra-normal levels of BAFF per se do not explain the phenotypic differences between B6.<i>Baff</i>^−/− and B6.<i>Br3</i>^−/− mice; (2) B cells are expanded in B6.<i>Taci</i>^−/− mice, with preferential expansion of follicular (FO) B cells at the expense of CD19⁺CD21^−/loCD23^−/lo B cells but without the preferential expansion of Foxp3⁺ cells observed in B6 mice bearing a <i>Baff</i> transgene; (3) despite no expansion in total B cells, percentages of FO B cells and marginal zone B cells are higher and percentages of CD19⁺CD21^−/loCD23^−/lo B cells are lower in young B6.<i>Bcma</i>^−/− mice, consistent with the inability of B6.<i>Br3</i>^−/−<i>.Taci</i>^−/− mice to recapitulate the B cell profile of B6.<i>Baff</i>^−/− mice; and (4) percentages of Foxp3⁺ cells in B6.<i>Br3</i>^−/−<i>.Taci</i>^−/− mice are intermediate between those in B6.<i>Br3</i>^−/− and B6.<i>Taci</i>^−/− mice despite the B cell profile of B6.<i>Br3</i>^−/−<i>.Taci</i>^−/− mice strongly resembling that of B6.<i>Br3</i>^−/− mice. Collectively, our findings point to a non-redundant role for each of the BAFF receptors in determining the ultimate lymphocyte profile of the host. This may have clinically relevant ramifications in that the degree that a candidate therapeutic agent blocks engagement of any given individual BAFF receptor may affect its clinical utility.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"173 4","pages":"689-711"},"PeriodicalIF":4.9,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imm.13856","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107021","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}

{"title":"Towards understanding the role of nanomedicine in targeting TNFR2 in rheumatoid arthritis","authors":"Fatmawati Lambuk,&nbsp;Nor Asyikin Nordin,&nbsp;Ali Mussa,&nbsp;Lidawani Lambuk,&nbsp;Suhana Ahmad,&nbsp;Rosline Hassan,&nbsp;Ramlah Kadir,&nbsp;Rohimah Mohamud,&nbsp;Nurul Khaiza Yahya","doi":"10.1111/imm.13855","DOIUrl":"10.1111/imm.13855","url":null,"abstract":"<p>Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation of the synovium and progressive joint destruction which significantly affects both quality of life and socioeconomic status. Admittedly, various treatments are available, but they are usually accompanied by various side effects, from mild to severe, and potentially with adverse events. Tumour necrosis factor-alpha (TNF-α) plays a crucial role in the pathophysiology of RA. It promotes inflammatory, apoptosis and necroptosis via TNF receptor-1 (TNFR1) but elicit anti-inflammatory effects via TNFR2. Herein, targeting TNFR2 has gained attention in RA studies. Understanding the role of nanomedicine in modulating TNFR2 signalling may be the instrument in development of RA therapies. Nanotechnology has made a significant progress in treating various conditions of diseases since its inception. Due to this, nanomedicine has emerged as a promising therapeutics approach for RA. Recent studies have demonstrated the potential of nanomedicine in RA theranostics, combining therapy and diagnostics for improved treatment outcomes. Owing to the challenges and advancements in the field of nanotechnology, nanoparticles are seen as an applicable candidate in the treatment of RA. In this review, we provide an overview of the role of nanomedicine in targeting TNFR2 for the treatment of RA and highlight the limitations of current therapies as well as the potential of nanocarriers with controlled drug release and active targeting abilities.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"173 4","pages":"622-633"},"PeriodicalIF":4.9,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imm.13855","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080196","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}

{"title":"Hypoxic tumour-derived exosomal miR-1290 exacerbates the suppression of CD8+ T cells by promoting M2 macrophage polarization","authors":"Yeni Yang,&nbsp;Tiansong Wu,&nbsp;Youpeng Wang,&nbsp;Dingan Luo,&nbsp;Ziyin Zhao,&nbsp;Hongfa Sun,&nbsp;Mao Zhang,&nbsp;Bin Zhang,&nbsp;Bing Han","doi":"10.1111/imm.13853","DOIUrl":"10.1111/imm.13853","url":null,"abstract":"<p>Hypoxia plays an important role in the metastasis of hepatocellular carcinoma (HCC). Exosomes have been widely studied as mediators of communication between tumours and immune cells. However, the specific mechanism by which hypoxic HCC cell-derived exosomes suppress antitumor immunity is unclear. Hypoxia scores were determined for The Cancer Genome-Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset patients, and HCC patients in the hyperhypoxic group had a higher degree of M2 macrophage infiltration. Patients in the M2 high-invasion group had a lower probability of survival than those in the low-invasion group. In vivo and in vitro experiments demonstrated that exosomes secreted by hypoxic HCC cells promote M2 macrophage polarization. This polarization induces apoptosis in CD8+ T cells. Additionally, it encourages epithelial–mesenchymal transition (EMT), which increases HCC migration. Exosomal miRNA sequencing revealed that miR-1290 was highly expressed in exosomes secreted by hypoxic HCC cells. Mechanistically, miR-1290 in macrophages inhibited Akt2 while upregulating PD-L1 to promote M2 polarization, induce apoptosis in CD8⁺ T cells, and enhance EMT in HCC. Animal studies found that the miR-1290 antagomir in combination with the immune checkpoint inhibitor produced better antitumor effects than the monotherapies. In conclusion, the secretion of exosome-derived miR-1290 from HCC cells in a hypoxic environment supported immune escape by HCC cells by promoting M2 macrophage polarization to induce apoptosis in CD8⁺ T cells and enhance EMT that promoted HCC metastasis. Therefore, miR-1290 is an important molecule in antitumor immunity in HCC, and inhibition of miR-1290 could provide a novel immunotherapeutic approach for HCC treatment.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"173 4","pages":"672-688"},"PeriodicalIF":4.9,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055476","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}

{"title":"Microscopic marvels: Decoding the role of micropeptides in innate immunity","authors":"Praveena Naidu,&nbsp;Mandë Holford","doi":"10.1111/imm.13850","DOIUrl":"10.1111/imm.13850","url":null,"abstract":"<p>The innate immune response is under selection pressures from changing environments and pathogens. While sequence evolution can be studied by comparing rates of amino acid mutations within and between species, how a gene's birth and death contribute to the evolution of immunity is less known. Short open reading frames, once regarded as untranslated or transcriptional noise, can often produce micropeptides of &lt;100 amino acids with a wide array of biological functions. Some micropeptide sequences are well conserved, whereas others have no evolutionary conservation, potentially representing new functional compounds that arise from species-specific adaptations. To date, few reports have described the discovery of novel micropeptides of the innate immune system. The diversity of immune-related micropeptides is a blind spot for gene and functional annotation. Immune-related micropeptides represent a potential reservoir of untapped compounds for understanding and treating disease. This review consolidates what is currently known about the evolution and function of innate immune-related micropeptides to facilitate their investigation.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"173 4","pages":"605-621"},"PeriodicalIF":4.9,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imm.13850","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072704","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}

{"title":"Altered epitopes enhance macrophage-mediated anti-tumour immunity to low-immunogenic tumour mutations","authors":"Qiumin Yu,&nbsp;Tingran Zhang,&nbsp;Tiandi He,&nbsp;Yifan Yang,&nbsp;Wanli Zhang,&nbsp;Yanliang Kang,&nbsp;Zijie Wu,&nbsp;Wenbin Xie,&nbsp;Jiaxue Zheng,&nbsp;Qianqian Qian,&nbsp;Guozhi Li,&nbsp;Di Zhang,&nbsp;Qiuli Mao,&nbsp;Zheng Gao,&nbsp;Xiaoning Wang,&nbsp;Xupeiyao Shi,&nbsp;Shitong Huang,&nbsp;Hanlin Guo,&nbsp;Haoyu Zhang,&nbsp;Lingxiao Chen,&nbsp;Ximing Li,&nbsp;Danni Deng,&nbsp;Li Zhang,&nbsp;Yue Tong,&nbsp;Wenbing Yao,&nbsp;Xiangdong Gao,&nbsp;Hong Tian","doi":"10.1111/imm.13854","DOIUrl":"10.1111/imm.13854","url":null,"abstract":"<p>Personalized neoantigen therapy has shown long-term and stable efficacy in specific patient populations. However, not all patients have sufficient levels of neoantigens for treatment. Although somatic mutations are commonly found in tumours, a significant portion of these mutations do not trigger an immune response. Patients with low mutation burdens continue to exhibit unresponsiveness to this treatment. We propose a design paradigm for neoantigen vaccines by utilizing the highly immunogenic unnatural amino acid p-nitrophenylalanine (pNO₂Phe) for sequence alteration of somatic mutations that failed to generate neoepitopes. This enhances the immunogenicity of the mutations and transforms it into a suitable candidate for immunotherapy. The nitrated altered epitope vaccines designed according to this paradigm is capable of activating circulating CD8⁺ T cells and inducing immune cross-reactivity against autologous mutated epitopes in different MHC backgrounds (H-2K^b, H-2K^d, and human HLA-A02:01), leading to the elimination of tumour cells carrying the mutation. After immunization with the altered epitopes, tumour growth was significantly inhibited. It is noteworthy that nitrated epitopes induce tumour-infiltrating macrophages to differentiate into the M1 phenotype, surprisingly enhancing the MHC II molecule presenting pathway of macrophages. Nitrated epitope-treated macrophages have the potential to cross-activate CD4⁺ and CD8⁺ T cells, which may explain why pNO₂Phe can enhance the immunogenicity of epitopes. Meanwhile, the immunosuppressive microenvironment of the tumour is altered due to the activation of macrophages. The nitrated neoantigen vaccine strategy enables the design of vaccines targeting non-immunogenic tumour mutations, expanding the pool of potential peptides for personalized and shared novel antigen therapy. This approach provides treatment opportunities for patients previously ineligible for new antigen vaccine therapy.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"173 4","pages":"654-671"},"PeriodicalIF":4.9,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035754","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}