ImmunoHorizons最新文献

{"title":"Dual TCR-Expressing T Cells in Cancer: How Single-Cell Technologies Enable New Investigation.","authors":"Elizabeth M Muhowski, Laura M Rogers","doi":"10.4049/immunohorizons.2200062","DOIUrl":"10.4049/immunohorizons.2200062","url":null,"abstract":"<p><p>TCR diversity measures are often used to understand the immune response in cancer. Traditional measures of diversity rely on bulk RNA sequencing (RNAseq) of the β-chain variable regions. However, the full αβ TCR repertoire is a combination of both the α- and β-chains, which are encoded by separate genes. In contrast with bulk RNAseq, single-cell RNAseq (scRNAseq) allows paired chain analyses, yielding a more accurate measure of the repertoire. Interestingly, ∼30% of mature peripheral T cells express multiple TCR alleles (e.g., two α-chains) and may exhibit dual Ag specificity. scRNAseq has become increasingly common, and data from both human and animal studies are publicly available. However, routine workflows discard secondary TCR alleles and focus on a single TCR clone per cell. This perspectives piece emphasizes why this may not be good practice and highlights unanswered questions in the field of T cell dual specificity.</p>","PeriodicalId":13448,"journal":{"name":"ImmunoHorizons","volume":"7 5","pages":"299-306"},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10354877/pdf/nihms-1915333.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9831552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Plasma Cell Infiltrate Populating the Muscle Tissue of Patients with Inclusion Body Myositis Features Distinct B Cell Receptor Repertoire Properties.","authors":"Roy Jiang, Bhaskar Roy, Qian Wu, Subhasis Mohanty, Richard J Nowak, Albert C Shaw, Steven H Kleinstein, Kevin C O'Connor","doi":"10.4049/immunohorizons.2200078","DOIUrl":"10.4049/immunohorizons.2200078","url":null,"abstract":"<p><p>Inclusion body myositis (IBM) is an autoimmune and degenerative disorder of skeletal muscle. The B cell infiltrates in IBM muscle tissue are predominantly fully differentiated Ab-secreting plasma cells, with scarce naive or memory B cells. The role of this infiltrate in the disease pathology is not well understood. To better define the humoral response in IBM, we used adaptive immune receptor repertoire sequencing, of human-derived specimens, to generate large BCR repertoire libraries from IBM muscle biopsies and compared them to those generated from dermatomyositis, polymyositis, and circulating CD27+ memory B cells, derived from healthy controls and Ab-secreting cells collected following vaccination. The repertoire properties of the IBM infiltrate included the following: clones that equaled or exceeded the highly clonal vaccine-associated Ab-secreting cell repertoire in size; reduced somatic mutation selection pressure in the CDRs and framework regions; and usage of class-switched IgG and IgA isotypes, with a minor population of IgM-expressing cells. The IBM IgM-expressing population revealed unique features, including an elevated somatic mutation frequency and distinct CDR3 physicochemical properties. These findings demonstrate that some of IBM muscle BCR repertoire characteristics are distinct from dermatomyositis and polymyositis and circulating Ag-experienced subsets, suggesting that it may form through selection by disease-specific Ags.</p>","PeriodicalId":13448,"journal":{"name":"ImmunoHorizons","volume":"7 5","pages":"310-322"},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9a/f3/ih2200078.PMC10579972.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9511307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SRF617 Is a Potent Inhibitor of CD39 with Immunomodulatory and Antitumor Properties.","authors":"Michael C Warren,&nbsp;Stephan Matissek,&nbsp;Matthew Rausch,&nbsp;Marisella Panduro,&nbsp;R J Hall,&nbsp;Austin Dulak,&nbsp;David Brennan,&nbsp;Sonia Das Yekkirala,&nbsp;Secil Koseoglu,&nbsp;Ricard Masia,&nbsp;Yu Yang,&nbsp;Navamallika Reddy,&nbsp;Robert Prenovitz,&nbsp;Jamie Strand,&nbsp;Tauqueer Zaidi,&nbsp;Erik Devereaux,&nbsp;Célia Jacoberger Foissac,&nbsp;John Stagg,&nbsp;Benjamin H Lee,&nbsp;Pamela Holland,&nbsp;Vito J Palombella,&nbsp;Andrew C Lake","doi":"10.4049/immunohorizons.2200089","DOIUrl":"10.4049/immunohorizons.2200089","url":null,"abstract":"<p><p>CD39 (ENTPD1) is a key enzyme responsible for degradation of extracellular ATP and is upregulated in the tumor microenvironment (TME). Extracellular ATP accumulates in the TME from tissue damage and immunogenic cell death, potentially initiating proinflammatory responses that are reduced by the enzymatic activity of CD39. Degradation of ATP by CD39 and other ectonucleotidases (e.g., CD73) results in extracellular adenosine accumulation, constituting an important mechanism for tumor immune escape, angiogenesis induction, and metastasis. Thus, inhibiting CD39 enzymatic activity can inhibit tumor growth by converting a suppressive TME to a proinflammatory environment. SRF617 is an investigational, anti-CD39, fully human IgG4 Ab that binds to human CD39 with nanomolar affinity and potently inhibits its ATPase activity. In vitro functional assays using primary human immune cells demonstrate that inhibiting CD39 enhances T-cell proliferation, dendritic cell maturation/activation, and release of IL-1β and IL-18 from macrophages. In vivo, SRF617 has significant single-agent antitumor activity in human cell line-derived xenograft models that express CD39. Pharmacodynamic studies demonstrate that target engagement of CD39 by SRF617 in the TME inhibits ATPase activity, inducing proinflammatory mechanistic changes in tumor-infiltrating leukocytes. Syngeneic tumor studies using human CD39 knock-in mice show that SRF617 can modulate CD39 levels on immune cells in vivo and can penetrate the TME of an orthotopic tumor, leading to increased CD8+ T-cell infiltration. Targeting CD39 is an attractive approach for treating cancer, and, as such, the properties of SRF617 make it an excellent drug development candidate.</p>","PeriodicalId":13448,"journal":{"name":"ImmunoHorizons","volume":"7 5","pages":"366-379"},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10579980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9651600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Our Shared Immunity.","authors":"Mark H Kaplan","doi":"10.4049/immunohorizons.2300033","DOIUrl":"10.4049/immunohorizons.2300033","url":null,"abstract":"","PeriodicalId":13448,"journal":{"name":"ImmunoHorizons","volume":"7 5","pages":"364-365"},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ce/0f/ih2300033.PMC10579979.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9878856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"B Cell Chronic Lymphocytic Leukemia Development in Mice with Chronic Lung Exposure to Coccidioides Fungal Arthroconidia.","authors":"Vanessa Coyne,&nbsp;Heather L Mead,&nbsp;Patricia K A Mongini,&nbsp;Bridget M Barker","doi":"10.4049/immunohorizons.2300013","DOIUrl":"10.4049/immunohorizons.2300013","url":null,"abstract":"<p><p>Links between repeated microbial infections and B cell chronic lymphocytic leukemia (B-CLL) have been proposed but not tested directly. This study examines how prolonged exposure to a human fungal pathogen impacts B-CLL development in Eµ-hTCL1-transgenic mice. Monthly lung exposure to inactivated Coccidioides arthroconidia, agents of Valley fever, altered leukemia development in a species-specific manner, with Coccidioides posadasii hastening B-CLL diagnosis/progression in a fraction of mice and Coccidioides immitis delaying aggressive B-CLL development, despite fostering more rapid monoclonal B cell lymphocytosis. Overall survival did not differ significantly between control and C. posadasii-treated cohorts but was significantly extended in C. immitis-exposed mice. In vivo doubling time analyses of pooled B-CLL showed no difference in growth rates of early and late leukemias. However, within C. immitis-treated mice, B-CLL manifests longer doubling times, as compared with B-CLL in control or C. posadasii-treated mice, and/or evidence of clonal contraction over time. Through linear regression, positive relationships were noted between circulating levels of CD5+/B220low B cells and hematopoietic cells previously linked to B-CLL growth, albeit in a cohort-specific manner. Neutrophils were positively linked to accelerated growth in mice exposed to either Coccidioides species, but not in control mice. Conversely, only C. posadasii-exposed and control cohorts displayed positive links between CD5+/B220low B cell frequency and abundance of M2 anti-inflammatory monocytes and T cells. The current study provides evidence that chronic lung exposure to fungal arthroconidia affects B-CLL development in a manner dependent on fungal genotype. Correlative studies suggest that fungal species differences in the modulation of nonleukemic hematopoietic cells are involved.</p>","PeriodicalId":13448,"journal":{"name":"ImmunoHorizons","volume":"7 5","pages":"333-352"},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/13/2d/ih2300013.PMC10579974.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9502697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune Dysfunction in Polycystic Ovary Syndrome.","authors":"Soma Banerjee, Laura G Cooney, Aleksandar K Stanic","doi":"10.4049/immunohorizons.2200033","DOIUrl":"10.4049/immunohorizons.2200033","url":null,"abstract":"<p><p>Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged individuals with ovaries. It is associated with anovulation and increased risk to fertility and metabolic, cardiovascular, and psychological health. The pathophysiology of PCOS is still inadequately understood, although there is evidence of persistent low-grade inflammation, which correlates with associated visceral obesity. Elevated proinflammatory cytokine markers and altered immune cells have been reported in PCOS and raise the possibility that immune factors contribute to ovulatory dysfunction. Because normal ovulation is modulated by immune cells and cytokines in the ovarian microenvironment, the endocrine and metabolic abnormalities associated with PCOS orchestrate the accompanying adverse effects on ovulation and implantation. This review evaluates the current literature on the relationship between PCOS and immune abnormalities, with a focus on emerging research in the field.</p>","PeriodicalId":13448,"journal":{"name":"ImmunoHorizons","volume":"7 5","pages":"323-332"},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10579973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9502699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evidence for Aerosol Transfer of SARS-CoV-2-Specific Humoral Immunity.","authors":"Ross M Kedl,&nbsp;Elena W Y Hsieh,&nbsp;Thomas E Morrison,&nbsp;Gabriela Samayoa-Reyes,&nbsp;Siobhan Flaherty,&nbsp;Conner L Jackson,&nbsp;Rosemary Rochford","doi":"10.4049/immunohorizons.2300027","DOIUrl":"10.4049/immunohorizons.2300027","url":null,"abstract":"<p><p>Infectious particles can be shared through aerosols and droplets formed as the result of normal respiration. Whether Abs within the nasal/oral fluids can similarly be shared between hosts has not been investigated. The circumstances of the SARS-CoV-2 pandemic facilitated a unique opportunity to fully examine this provocative idea. The data we show from human nasal swabs provides evidence for the aerosol transfer of Abs between immune and nonimmune hosts.</p>","PeriodicalId":13448,"journal":{"name":"ImmunoHorizons","volume":"7 5","pages":"307-309"},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10579981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9511293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Negative Data, Oh No What Should I Do? How Publication of Negative Data Removes Roadblocks to Productive Research from the Perspective of Scientists Who Perform the Experiments.","authors":"Angela K Beltrame,&nbsp;Johnathon J Caldon,&nbsp;Cody J Gurski,&nbsp;Zivar Hajiyeva,&nbsp;Nathan J Meinhardt,&nbsp;Kelli C Sommers,&nbsp;Savannah D Neu,&nbsp;Bonnie N Dittel","doi":"10.4049/immunohorizons.2300032","DOIUrl":"10.4049/immunohorizons.2300032","url":null,"abstract":".","PeriodicalId":13448,"journal":{"name":"ImmunoHorizons","volume":"7 5","pages":"380-383"},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10414161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9967573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How the Unfolded Protein Response Is a Boon for Tumors and a Bane for the Immune System.","authors":"Lydia N Raines, Stanley Ching-Cheng Huang","doi":"10.4049/immunohorizons.2200064","DOIUrl":"10.4049/immunohorizons.2200064","url":null,"abstract":"<p><p>The correct folding of proteins is essential for appropriate cell function and is tightly regulated within the endoplasmic reticulum (ER). Environmental challenges and cellular conditions disrupt ER homeostasis and induce ER stress, which adversely affect protein folding and activate the unfolded protein response (UPR). It is now becoming recognized that cancer cells can overcome survival challenges posed within the tumor microenvironment by activating the UPR. Furthermore, the UPR has also been found to impose detrimental effects on immune cells by inducing immunoinhibitory activity in both tumor-infiltrating innate and adaptive immune cells. This suggests that these signaling axes may be important therapeutic targets, resulting in multifaceted approaches to eradicating tumor cells. In this mini-review, we discuss the role of the UPR in driving tumor progression and modulating the immune system's ability to target cancer cells. Additionally, we highlight some of the key unanswered questions that may steer future UPR research.</p>","PeriodicalId":13448,"journal":{"name":"ImmunoHorizons","volume":"7 4","pages":"256-264"},"PeriodicalIF":0.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10579845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9465235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guselkumab More Effectively Neutralizes Psoriasis-Associated Histologic, Transcriptomic, and Clinical Measures than Ustekinumab.","authors":"Kim Campbell,&nbsp;Katherine Li,&nbsp;Feifei Yang,&nbsp;Patrick Branigan,&nbsp;M Merle Elloso,&nbsp;Jacqueline Benson,&nbsp;Yevgeniya Orlovsky,&nbsp;Yanqing Chen,&nbsp;Sandra Garcet,&nbsp;James G Krueger","doi":"10.4049/immunohorizons.2300003","DOIUrl":"10.4049/immunohorizons.2300003","url":null,"abstract":"<p><p>Given the key role of the IL-23/Th17 axis in the pathogenesis of moderate-to-severe plaque psoriasis, several specific inhibitors of the p19 subunit of IL-23 have been approved to treat this chronic inflammatory disease. Clinical data indicate that guselkumab, one such selective IL-23 inhibitor, achieves greater clinical efficacy compared with ustekinumab, which inhibits both IL-12 and IL-23 via binding their shared p40 subunit. To understand mechanisms underlying the enhanced efficacy observed with the p19 subunit of IL-23-specific inhibition, we explored cellular and molecular changes in skin of psoriasis patients treated with ustekinumab or guselkumab and in ustekinumab inadequate responders (Investigator's Global Assessment of psoriasis score ≥ 2) subsequently treated with guselkumab (ustekinumab→guselkumab). Skin biopsies were collected pretreatment and posttreatment to assess histologic changes and molecular responses in ustekinumab- and guselkumab-treated patients. Serum cytokines and skin transcriptomics from the subset of ustekinumab→guselkumab-treated patients were also analyzed to characterize differential treatment effects. Ustekinumab and guselkumab demonstrated differential effects on secretion of pathogenic Th17-related cytokines induced by IL-23 in in vitro assays, which suggest guselkumab is a more potent therapeutic agent. Consistent with these findings, guselkumab elicited a significantly greater reduction in cellular and molecular psoriasis-related disease indicators than ustekinumab. In ustekinumab→guselkumab patients, suppression of serum IL-17A and IL-17F levels and neutralization of molecular scar and psoriasis-related gene markers in skin were significantly greater compared with patients continuing ustekinumab. This comparative study demonstrates that guselkumab inhibits psoriasis-associated pathology, suppresses Th17-related serum cytokines, and normalizes the psoriasis skin gene expression profile more effectively than ustekinumab.</p>","PeriodicalId":13448,"journal":{"name":"ImmunoHorizons","volume":"7 4","pages":"273-285"},"PeriodicalIF":0.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9d/64/ih2300003.PMC10579843.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9401567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}