Despite great strides of progress, at least 60% of the responding patients relapse to CAR therapy across the blood malignancies. Off-tumor toxicity apart from functional deficits, cytopenia and infection are the major unfavourable effect of CAR therapy. Models, which faithfully recapitulate the physiology and complexities of immunocompetent tumor microenvironment (TME), paused challenges in capturing potential off-tumor effects of CAR therapy. Importantly, a landmark change in the legislation allows US Food and Drug Administration and New Drugs and Clinical Trial Rules in India encourages researchers to replace animal testing with cell culture approaches relevant to human system. Organ-on-chip (OOC) based on microfluidics technology can potentially emulate multiple biochemical and biophysical intricacies of blood and lymph flow at microscale. Nonetheless, how the evolving microfluidics technology can be enabling to real-time testing of cell and gene is yet to be realised.
{"title":"Organ-on-chip for advancing CAR therapy","authors":"Lightson Ngashangva, Sunil Martin","doi":"10.1002/cti2.70024","DOIUrl":"https://doi.org/10.1002/cti2.70024","url":null,"abstract":"<p>Despite great strides of progress, at least 60% of the responding patients relapse to CAR therapy across the blood malignancies. Off-tumor toxicity apart from functional deficits, cytopenia and infection are the major unfavourable effect of CAR therapy. Models, which faithfully recapitulate the physiology and complexities of immunocompetent tumor microenvironment (TME), paused challenges in capturing potential off-tumor effects of CAR therapy. Importantly, a landmark change in the legislation allows US Food and Drug Administration and New Drugs and Clinical Trial Rules in India encourages researchers to replace animal testing with cell culture approaches relevant to human system. Organ-on-chip (OOC) based on microfluidics technology can potentially emulate multiple biochemical and biophysical intricacies of blood and lymph flow at microscale. Nonetheless, how the evolving microfluidics technology can be enabling to real-time testing of cell and gene is yet to be realised.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 2","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70024","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143489966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nicole L Messina, Susie Germano, Amy W Chung, Carolien E van de Sandt, Natalie E Stevens, Lilith F Allen, Rhian Bonnici, Julio Croda, Claudio Counoupas, Branka Grubor-Bauk, Ebene R Haycroft, Katherine Kedzierska, Ellie McDonald, Rebecca McElroy, Mihai G Netea, Boris Novakovic, Kirsten P Perrett, Laure F Pittet, Ruth A Purcell, Kanta Subbarao, James A Triccas, David J Lynn, Nigel Curtis, the BRACE Trial Consortium Group
Objectives
Bacille Calmette–Guérin (BCG) vaccination has off-target effects on disease risk for unrelated infections and immune responses to vaccines. This study aimed to determine the immunomodulatory effects of BCG vaccination on immune responses to vaccines against SARS-CoV-2.
Methods
Blood samples, from a subset of 275 SARS-CoV-2-naïve healthcare workers randomised to BCG vaccination (BCG group) or no BCG vaccination (Control group) in the BRACE trial, were collected before and 28 days after the primary course (two doses) of ChAdOx1-S (Oxford-AstraZeneca) or BNT162b2 (Pfizer-BioNTech) vaccination. SARS-CoV-2-specific antibodies were measured using ELISA and multiplex bead array, whole blood cytokine responses to γ-irradiated SARS-CoV-2 (iSARS) stimulation were measured by multiplex bead array, and SARS-CoV-2-specific T-cell responses were measured by activation-induced marker and intracellular cytokine staining assays.
Results
After randomisation (mean 11 months) but prior to COVID-19 vaccination, the BCG group had lower cytokine responses to iSARS stimulation than the Control group. After two doses of ChAdOx1-S, differences in iSARS-induced cytokine responses between the BCG group and Control group were found for three cytokines (CTACK, TRAIL and VEGF). No differences were found between the groups after BNT162b2 vaccination. There were also no differences between the BCG and Control groups in COVID-19 vaccine-induced antigen-specific antibody responses, T-cell activation or T-cell cytokine production.
Conclusion
BCG vaccination induced a broad and persistent reduction in ex vivo cytokine responses to SARS-CoV-2. Following COVID-19 vaccination, this effect was abrogated, and BCG vaccination did not influence adaptive immune responses to COVID-19 vaccine antigens.
{"title":"Effect of Bacille Calmette–Guérin vaccination on immune responses to SARS-CoV-2 and COVID-19 vaccination","authors":"Nicole L Messina, Susie Germano, Amy W Chung, Carolien E van de Sandt, Natalie E Stevens, Lilith F Allen, Rhian Bonnici, Julio Croda, Claudio Counoupas, Branka Grubor-Bauk, Ebene R Haycroft, Katherine Kedzierska, Ellie McDonald, Rebecca McElroy, Mihai G Netea, Boris Novakovic, Kirsten P Perrett, Laure F Pittet, Ruth A Purcell, Kanta Subbarao, James A Triccas, David J Lynn, Nigel Curtis, the BRACE Trial Consortium Group","doi":"10.1002/cti2.70023","DOIUrl":"10.1002/cti2.70023","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Bacille Calmette–Guérin (BCG) vaccination has off-target effects on disease risk for unrelated infections and immune responses to vaccines. This study aimed to determine the immunomodulatory effects of BCG vaccination on immune responses to vaccines against SARS-CoV-2.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Blood samples, from a subset of 275 SARS-CoV-2-naïve healthcare workers randomised to BCG vaccination (BCG group) or no BCG vaccination (Control group) in the BRACE trial, were collected before and 28 days after the primary course (two doses) of ChAdOx1-S (Oxford-AstraZeneca) or BNT162b2 (Pfizer-BioNTech) vaccination. SARS-CoV-2-specific antibodies were measured using ELISA and multiplex bead array, whole blood cytokine responses to γ-irradiated SARS-CoV-2 (iSARS) stimulation were measured by multiplex bead array, and SARS-CoV-2-specific T-cell responses were measured by activation-induced marker and intracellular cytokine staining assays.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>After randomisation (mean 11 months) but prior to COVID-19 vaccination, the BCG group had lower cytokine responses to iSARS stimulation than the Control group. After two doses of ChAdOx1-S, differences in iSARS-induced cytokine responses between the BCG group and Control group were found for three cytokines (CTACK, TRAIL and VEGF). No differences were found between the groups after BNT162b2 vaccination. There were also no differences between the BCG and Control groups in COVID-19 vaccine-induced antigen-specific antibody responses, T-cell activation or T-cell cytokine production.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>BCG vaccination induced a broad and persistent reduction in <i>ex vivo</i> cytokine responses to SARS-CoV-2. Following COVID-19 vaccination, this effect was abrogated, and BCG vaccination did not influence adaptive immune responses to COVID-19 vaccine antigens.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eleni Tiniakou, Livia Casciola-Rosen, Mekha A Thomas, Yuka Manabe, Annukka AR Antar, Mahendra Damarla, Paul M Hassoun, Li Gao, Zitong Wang, Scott Zeger, Antony Rosen
Objectives
CD209L and its homologous protein CD209 act as alternative entry receptors for the SARS-CoV-2 virus and are highly expressed in the virally targeted tissues. We tested for the presence and clinical features of autoantibodies targeting these receptors and compared these with autoantibodies known to be associated with COVID-19.
Methods
Using banked samples (n = 118) from Johns Hopkins patients hospitalised with COVID-19, we defined autoantibodies against CD209 and CD209L by enzyme-linked immunosorbent assay (ELISA). Clinical associations of these antibodies were compared with those of patients with anti-interferon (IFN) and anti-angiotensin-converting enzyme-2 (ACE2) autoantibodies.
Results
Amongst patients hospitalised with COVID-19, 19.5% (23/118) had IgM autoantibodies against CD209L and were more likely to have coronary artery disease (44% vs 19%, P = 0.03). Antibodies against CD209 were present in 5.9% (7/118); interestingly, all 7 were male (P = 0.02). In our study, the presence of either antibody was positively associated with disease severity [OR 95% confidence interval (95% CI): 1.80 (0.69–5.03)], but the association did not reach statistical significance. In contrast, 10/118 (8.5%) had IgG autoantibodies against IFNα, and 21 (17.8%) had IgM antibodies against ACE2. These patients had significantly worse prognosis (intubation or death) and prolonged hospital stays. However, when adjusting for patient characteristics on admission, only the presence of anti-ACE2 IgM remained significant [pooled common OR (95% CI), 4.14 (1.37, 12.54)].
Conclusion
We describe IgM autoantibodies against CD209 and CD209L amongst patients hospitalised with COVID-19. These were not associated with disease severity. Conversely, patients with either anti-ACE2 IgM or anti-IFNα IgG antibodies had worse outcomes. Due to the small size of the study cohort, conclusions drawn should be considered cautiously.
{"title":"Autoantibodies in hospitalised patients with COVID-19","authors":"Eleni Tiniakou, Livia Casciola-Rosen, Mekha A Thomas, Yuka Manabe, Annukka AR Antar, Mahendra Damarla, Paul M Hassoun, Li Gao, Zitong Wang, Scott Zeger, Antony Rosen","doi":"10.1002/cti2.70019","DOIUrl":"10.1002/cti2.70019","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>CD209L and its homologous protein CD209 act as alternative entry receptors for the SARS-CoV-2 virus and are highly expressed in the virally targeted tissues. We tested for the presence and clinical features of autoantibodies targeting these receptors and compared these with autoantibodies known to be associated with COVID-19.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using banked samples (<i>n</i> = 118) from Johns Hopkins patients hospitalised with COVID-19, we defined autoantibodies against CD209 and CD209L by enzyme-linked immunosorbent assay (ELISA). Clinical associations of these antibodies were compared with those of patients with anti-interferon (IFN) and anti-angiotensin-converting enzyme-2 (ACE2) autoantibodies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Amongst patients hospitalised with COVID-19, 19.5% (23/118) had IgM autoantibodies against CD209L and were more likely to have coronary artery disease (44% vs 19%, <i>P</i> = 0.03). Antibodies against CD209 were present in 5.9% (7/118); interestingly, all 7 were male (<i>P</i> = 0.02). In our study, the presence of either antibody was positively associated with disease severity [OR 95% confidence interval (95% CI): 1.80 (0.69–5.03)], but the association did not reach statistical significance. In contrast, 10/118 (8.5%) had IgG autoantibodies against IFNα, and 21 (17.8%) had IgM antibodies against ACE2. These patients had significantly worse prognosis (intubation or death) and prolonged hospital stays. However, when adjusting for patient characteristics on admission, only the presence of anti-ACE2 IgM remained significant [pooled common OR (95% CI), 4.14 (1.37, 12.54)].</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We describe IgM autoantibodies against CD209 and CD209L amongst patients hospitalised with COVID-19. These were not associated with disease severity. Conversely, patients with either anti-ACE2 IgM or anti-IFNα IgG antibodies had worse outcomes. Due to the small size of the study cohort, conclusions drawn should be considered cautiously.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 12","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dan Wang, Liuyang Wang, Shuai Liu, Jianjun Tong, Honglin Zhu, Man Xu, Xiancai Li, Zhiqiang Xiang, Qinghua Sun, Hengcai Wang, Yuli Wang, Shuyang Wang, Liming Yang
Objectives
To evaluate the manufacturability, efficacy and safety of allogeneic CD19 chimeric antigen receptor double-negative T cells (CD19-CAR-DNTs) as an off-the-shelf therapeutic cell product.
Methods
A membrane proteome array was used to assess the off-target binding of CD19-CAR. DNTs derived from healthy donors were transduced with lentiviral vectors encoding the CD19-CAR. The manufacture of the CD19-CAR-DNTs was under GMP conditions, and their surface molecule expression patterns were characterised using flow cytometry. We investigated the off-the-shelf potential of CD19-CAR-DNTs by evaluating the cryopreserved CD19-CAR-DNTs in terms of cell viability as well as their cytotoxicity against various CD19+ target cell lines and primary patient blasts in vitro. We evaluated the persistence and safety of the cryopreserved CD19-CAR-DNTs in xenograft models in vivo.
Results
GMP-grade CD19-CAR-DNTs were manufactured and cryopreserved for use in advance. The cryopreserved CD19-CAR-DNTs maintain their viability and antitumor activity against various CD19+ target cell lines and primary patient blasts. These cells significantly prolonged the survival in Raji-Luc-xenografted NOG mice. Multiple infusions of the cells can further augment their efficacy. Remarkably, following a single infusion in mice, CD19-CAR-DNTs rapidly got distributed among well-perfused organs initially, and progressively spread to most tissues, peaking at Day 43. In toxicity studies, CD19-CAR-DNTs significantly reduced tumor burden and ameliorated tissue damage in tumor-bearing NOG mice. Critically, no immunotoxicity or graft versus host disease was observed in non-tumor-bearing NOG mice.
Conclusions
The allogeneic CD19-CAR-DNTs fulfil the requirements of an off-the-shelf therapeutic cell product, offering a promising new approach to the treatment of haematological malignancies.
目的：评价同种异体CD19嵌合抗原受体双阴性T细胞（CD19- car - dnts）作为一种现成的治疗细胞产品的可制造性、有效性和安全性。方法：采用膜蛋白质组阵列检测CD19-CAR的脱靶结合。用编码CD19-CAR的慢病毒载体转导来自健康供体的dnt。在GMP条件下制备CD19-CAR-DNTs，并使用流式细胞术表征其表面分子表达模式。我们通过在体外评估冷冻保存的CD19- car - dnts的细胞活力以及它们对各种CD19+靶细胞系和原代患者细胞的细胞毒性，研究了CD19- car - dnts的现成潜力。我们评估了冷冻保存的CD19-CAR-DNTs在体内异种移植模型中的持久性和安全性。结果：制备出gmp级CD19-CAR-DNTs并冷冻保存。冷冻保存的CD19- car - dnts对各种CD19+靶细胞系和原代患者原细胞保持活性和抗肿瘤活性。这些细胞显著延长了raji - luc异种移植NOG小鼠的存活时间。多次输注细胞可进一步增强其功效。值得注意的是，在小鼠体内单次输注后，CD19-CAR-DNTs最初迅速分布在灌注良好的器官中，并逐渐扩散到大多数组织，在第43天达到峰值。在毒性研究中，CD19-CAR-DNTs显著减轻了荷瘤NOG小鼠的肿瘤负荷并改善了组织损伤。关键的是，在非荷瘤NOG小鼠中没有观察到免疫毒性或移植物抗宿主病。结论：同种异体CD19-CAR-DNTs满足了一种现成的治疗细胞产品的要求，为治疗血液系统恶性肿瘤提供了一种有希望的新方法。
{"title":"A preclinical study of allogeneic CD19 chimeric antigen receptor double-negative T cells as an off-the-shelf immunotherapy drug against B-cell malignancies","authors":"Dan Wang, Liuyang Wang, Shuai Liu, Jianjun Tong, Honglin Zhu, Man Xu, Xiancai Li, Zhiqiang Xiang, Qinghua Sun, Hengcai Wang, Yuli Wang, Shuyang Wang, Liming Yang","doi":"10.1002/cti2.70022","DOIUrl":"10.1002/cti2.70022","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>To evaluate the manufacturability, efficacy and safety of allogeneic CD19 chimeric antigen receptor double-negative T cells (CD19-CAR-DNTs) as an off-the-shelf therapeutic cell product.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A membrane proteome array was used to assess the off-target binding of CD19-CAR. DNTs derived from healthy donors were transduced with lentiviral vectors encoding the CD19-CAR. The manufacture of the CD19-CAR-DNTs was under GMP conditions, and their surface molecule expression patterns were characterised using flow cytometry. We investigated the off-the-shelf potential of CD19-CAR-DNTs by evaluating the cryopreserved CD19-CAR-DNTs in terms of cell viability as well as their cytotoxicity against various CD19<sup>+</sup> target cell lines and primary patient blasts <i>in vitro.</i> We evaluated the persistence and safety of the cryopreserved CD19-CAR-DNTs in xenograft models <i>in vivo</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>GMP-grade CD19-CAR-DNTs were manufactured and cryopreserved for use in advance. The cryopreserved CD19-CAR-DNTs maintain their viability and antitumor activity against various CD19<sup>+</sup> target cell lines and primary patient blasts. These cells significantly prolonged the survival in Raji-Luc-xenografted NOG mice. Multiple infusions of the cells can further augment their efficacy. Remarkably, following a single infusion in mice, CD19-CAR-DNTs rapidly got distributed among well-perfused organs initially, and progressively spread to most tissues, peaking at Day 43. In toxicity studies, CD19-CAR-DNTs significantly reduced tumor burden and ameliorated tissue damage in tumor-bearing NOG mice. Critically, no immunotoxicity or graft versus host disease was observed in non-tumor-bearing NOG mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The allogeneic CD19-CAR-DNTs fulfil the requirements of an off-the-shelf therapeutic cell product, offering a promising new approach to the treatment of haematological malignancies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 12","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Daniel Álvarez, Hephzibah E Winter, Carlos J Velasquez Franco, Aleida Susana Castellanos Gutierrez, Núria Baños, Udo R Markert, Ángela P Cadavid, Diana M Morales-Prieto
Objectives
Antiphospholipid syndrome (APS) is an autoimmune disease driven by antiphospholipid antibodies (aPL). Currently, APS diagnosis requires a combination of clinical manifestations (thrombosis and/or obstetric morbidity) and the persistent presence of at least one criteria aPL: anti-cardiolipin antibodies (aCL), anti-β2-glycoprotein I antibodies (aβ2GPI) or lupus anticoagulant (LA). Patients with suggestive obstetric symptoms but lacking criteria aPL face diagnostic challenges. Non-criteria aPL screening may enhance discrimination. This study proposes a classification incorporating both criteria and non-criteria antibodies to improve obstetric APS diagnosis.
Methods
Blood samples from non-pregnant women (n = 68) with a history of vascular, obstetric, or vascular and obstetric manifestations were analysed. Among them, 30 had previous diagnosis of APS. Healthy women with proven gestational success were included as controls (n = 16). Criteria and non-criteria (anti-phosphatidylglycerol, anti-phosphatidylethanolamine, anti-phosphatidylinositol, anti-phosphatidylserine and anti-phosphatidic acid) IgG aPL were evaluated by ELISA and coagulation tests. Based on the resulting aPL profile, patients were reclassified. Responsiveness to treatment was obtained from medical records.
Results
Criteria aPL levels marginally differentiated women previously managed as obstetric APS from unexplained/other causes of obstetric morbidity. Including non-criteria aPL improved separation. The proposed classification identified an obstetric APS group that exhibits non-criteria aPL and aβ2GPI titres below the cut-off but higher than healthy women (7.88 vs. 2.47 SGU, P = 0.006). Compared to cases of other causes of obstetric morbidity, these patients retrospectively responded better to aspirin and/or heparin treatment (71.43% vs. 11.11%, P = 0.035).
Conclusions
Assessing non-criteria antibodies may identify isolated obstetric APS cases benefiting from established therapies.
目的：抗磷脂综合征（APS）是一种由抗磷脂抗体（aPL）驱动的自身免疫性疾病。目前，APS的诊断需要结合临床表现（血栓形成和/或产科发病）和至少一种标准aPL的持续存在：抗心磷脂抗体（aCL）、抗β2-糖蛋白I抗体（a -β 2gpi）或狼疮抗凝剂（LA）。有暗示性产科症状但缺乏标准aPL的患者面临诊断挑战。非标准aPL筛查可能增强歧视。本研究提出了一种结合标准和非标准抗体的分类，以改善产科APS诊断。方法：对有血管、产科病史或血管和产科表现的非妊娠妇女（n = 68）的血液样本进行分析。其中30例既往诊断为APS。经证实妊娠成功的健康妇女作为对照组（n = 16）。采用ELISA和凝血试验评价标准和非标准（抗磷脂酰甘油、抗磷脂酰乙醇胺、抗磷脂酰肌醇、抗磷脂酰丝氨酸和抗磷脂酸）IgG aPL。根据结果的aPL谱，对患者进行重新分类。从医疗记录中获得对治疗的反应性。结果：标准aPL水平将以前作为产科APS管理的妇女与不明原因/其他原因的产科发病率区分开来。包括非标准api改善了分离。建议的分类确定了一个产科APS组，其显示非标准aPL和aβ2GPI滴度低于临界值，但高于健康妇女（7.88 vs 2.47 SGU, P = 0.006）。与其他原因的产科发病病例相比，这些患者对阿司匹林和/或肝素治疗的回顾性反应更好（71.43%比11.11%,P = 0.035）。结论：评估非标准抗体可以识别孤立的产科APS病例受益于既定的治疗。
{"title":"Improving diagnosis in patients with obstetric antiphospholipid syndrome through the evaluation of non-criteria antibodies","authors":"Daniel Álvarez, Hephzibah E Winter, Carlos J Velasquez Franco, Aleida Susana Castellanos Gutierrez, Núria Baños, Udo R Markert, Ángela P Cadavid, Diana M Morales-Prieto","doi":"10.1002/cti2.70021","DOIUrl":"10.1002/cti2.70021","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Antiphospholipid syndrome (APS) is an autoimmune disease driven by antiphospholipid antibodies (aPL). Currently, APS diagnosis requires a combination of clinical manifestations (thrombosis and/or obstetric morbidity) and the persistent presence of at least one criteria aPL: anti-cardiolipin antibodies (aCL), anti-β2-glycoprotein I antibodies (aβ2GPI) or lupus anticoagulant (LA). Patients with suggestive obstetric symptoms but lacking criteria aPL face diagnostic challenges. Non-criteria aPL screening may enhance discrimination. This study proposes a classification incorporating both criteria and non-criteria antibodies to improve obstetric APS diagnosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Blood samples from non-pregnant women (<i>n</i> = 68) with a history of vascular, obstetric, or vascular and obstetric manifestations were analysed. Among them, 30 had previous diagnosis of APS. Healthy women with proven gestational success were included as controls (<i>n</i> = 16). Criteria and non-criteria (anti-phosphatidylglycerol, anti-phosphatidylethanolamine, anti-phosphatidylinositol, anti-phosphatidylserine and anti-phosphatidic acid) IgG aPL were evaluated by ELISA and coagulation tests. Based on the resulting aPL profile, patients were reclassified. Responsiveness to treatment was obtained from medical records.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Criteria aPL levels marginally differentiated women previously managed as obstetric APS from unexplained/other causes of obstetric morbidity. Including non-criteria aPL improved separation. The proposed classification identified an obstetric APS group that exhibits non-criteria aPL and aβ2GPI titres below the cut-off but higher than healthy women (7.88 vs. 2.47 SGU, <i>P</i> = 0.006). Compared to cases of other causes of obstetric morbidity, these patients retrospectively responded better to aspirin and/or heparin treatment (71.43% vs. 11.11%, <i>P</i> = 0.035).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Assessing non-criteria antibodies may identify isolated obstetric APS cases benefiting from established therapies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 12","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kazushige Obata-Ninomiya, Tharmalingam Jayaraman, Steven F Ziegler
Type 2 epithelial cytokines, including thymic stromal lymphopoietin and IL-33, play central roles in modulation of type 2 immune cells, such as basophils. Basophils are a small subset of granulocytes within the leukocyte population that predominantly exist in the blood. They have non-redundant roles in allergic inflammation in peripheral tissues such as the lung, skin and gut, where they increase and accumulate at inflammatory lesions and exclusively produce large amounts of IL-4, a type 2 cytokine. These inflammatory reactions are known to be, to some extent, phenocopies of infectious diseases of ticks and helminths. Recently, biologics related to both type 2 epithelial cytokines and basophils have been approved by the US Food and Drug Administration for treatment of allergic diseases. We summarised the roles of Type 2 epithelial cytokines and basophils in basic science to translational medicine, including recent findings.
{"title":"From the bench to the clinic: basophils and type 2 epithelial cytokines of thymic stromal lymphopoietin and IL-33","authors":"Kazushige Obata-Ninomiya, Tharmalingam Jayaraman, Steven F Ziegler","doi":"10.1002/cti2.70020","DOIUrl":"10.1002/cti2.70020","url":null,"abstract":"<p>Type 2 epithelial cytokines, including thymic stromal lymphopoietin and IL-33, play central roles in modulation of type 2 immune cells, such as basophils. Basophils are a small subset of granulocytes within the leukocyte population that predominantly exist in the blood. They have non-redundant roles in allergic inflammation in peripheral tissues such as the lung, skin and gut, where they increase and accumulate at inflammatory lesions and exclusively produce large amounts of IL-4, a type 2 cytokine. These inflammatory reactions are known to be, to some extent, phenocopies of infectious diseases of ticks and helminths. Recently, biologics related to both type 2 epithelial cytokines and basophils have been approved by the US Food and Drug Administration for treatment of allergic diseases. We summarised the roles of Type 2 epithelial cytokines and basophils in basic science to translational medicine, including recent findings.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 12","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11626414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Palak H Mehta, Gemma S Trollope, Patrick Leung, Shivali Savita Chinni, Anna Iasinskaia, Aaron J Harrison, Hannah Hughes-Parry, Misty R Jenkins, Michael H Kershaw, Anthony Jaworowski, Clare Y Slaney, Rachel M Koldej, David S Ritchie, Kylie M Quinn
Objectives
In clinical chimeric antigen receptor (CAR) T cell therapy, one of the strongest correlates of favorable patient responses is lower levels of differentiation in T cells from the peripheral blood mononuclear cell (PBMC) starting material or the CAR T cell product. T cells from older patients are inherently more differentiated, but we hypothesised that specific activation protocols could be used to limit CAR T cell differentiation during manufacturing, particularly in older patients.
Methods
We used PBMCs from young (20–30 years old) and older (60+ years old) healthy donors to generate CAR T cells using two activation protocols: soluble anti-(α) CD3 monoclonal antibody (mAb) vs immune complexes of αCD3 and αCD28 mAbs. Products were assessed for yield, function and differentiation, which was used as a measure of CAR T cell quality. T cells in PBMCs were assessed for CD28 expression and correlative analyses were performed.
Results
Older samples generated fewer, more differentiated CAR T cells than young samples, and the αCD3/CD28 mAb protocol exacerbated this, further reducing yield and quality. CD28 expression by T cells correlated with CAR T cell differentiation, but T cell differentiation in PBMC starting material was a stronger correlate of CAR T cell differentiation.
Conclusions
Choice of activation protocol can substantially impact on the yield and quality of CAR T cells during manufacturing. This is a key consideration for older patients whose samples already generate a poorer yield and lower quality of CAR T cells.
{"title":"Choice of activation protocol impacts the yield and quality of CAR T cell product, particularly with older individuals","authors":"Palak H Mehta, Gemma S Trollope, Patrick Leung, Shivali Savita Chinni, Anna Iasinskaia, Aaron J Harrison, Hannah Hughes-Parry, Misty R Jenkins, Michael H Kershaw, Anthony Jaworowski, Clare Y Slaney, Rachel M Koldej, David S Ritchie, Kylie M Quinn","doi":"10.1002/cti2.70016","DOIUrl":"https://doi.org/10.1002/cti2.70016","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>In clinical chimeric antigen receptor (CAR) T cell therapy, one of the strongest correlates of favorable patient responses is lower levels of differentiation in T cells from the peripheral blood mononuclear cell (PBMC) starting material or the CAR T cell product. T cells from older patients are inherently more differentiated, but we hypothesised that specific activation protocols could be used to limit CAR T cell differentiation during manufacturing, particularly in older patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used PBMCs from young (20–30 years old) and older (60+ years old) healthy donors to generate CAR T cells using two activation protocols: soluble anti-(α) CD3 monoclonal antibody (mAb) <i>vs</i> immune complexes of αCD3 and αCD28 mAbs. Products were assessed for yield, function and differentiation, which was used as a measure of CAR T cell quality. T cells in PBMCs were assessed for CD28 expression and correlative analyses were performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Older samples generated fewer, more differentiated CAR T cells than young samples, and the αCD3/CD28 mAb protocol exacerbated this, further reducing yield and quality. CD28 expression by T cells correlated with CAR T cell differentiation, but T cell differentiation in PBMC starting material was a stronger correlate of CAR T cell differentiation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Choice of activation protocol can substantially impact on the yield and quality of CAR T cells during manufacturing. This is a key consideration for older patients whose samples already generate a poorer yield and lower quality of CAR T cells.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 12","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thi Viet Trinh Dang, Kevin R Gillinder, Quan Nguyen, Onkar Mulay, Tuan Vo, Ahmed M Mehdi, Chenhao Zhou, Andrew J Brooks, Graham R Leggatt, David A Hume, Ian H Frazer, Janin Chandra
Objectives
Langerhans cells (LCs) are epithelial antigen-presenting cells (APC) contributing to immune surveillance. LCs depend on interleukin 34 (IL34) production by epithelial cells. This study aimed to uncover mechanisms of alteration of IL34 and LC function in squamous cell carcinoma (SCC).
Methods
Cancer cohort data were used to identify associations between SCC and IL34. ATAC-seq of keratinocytes (KCs) and LCs from a murine model of epithelial hyperplasia, driven by HPV16 E7 oncoprotein (K14E7), was analysed. Transcriptomic data were used to validate findings. RNAscope, RT-qPCR, ELISA and confocal imaging was used to analyse IL34 expression and LCs in a spatial context.
Results
IL34 mRNA is downregulated in human SCCs of the head and neck, the cervix, the lung and the oesophagus, and low IL34 expression is associated with poor survival. We demonstrate that KCs of K14E7 mice have reduced Il34 gene accessibility, mRNA and protein, as well as broad changes in promotor accessibility associated with cell adhesion and immune responses. Chromatin accessibility was substantially changed in LCs, including increased accessibility of the Csf1r gene, and changes in promotors associated with cytoskeleton arrangement and antigen processing and presentation. We discovered altered spatial LC dendrite organisation in hyperproliferative epithelium.
Conclusion
Squamous cell carcinoma of the cervix, head and neck, oesophagus and lung demonstrate downregulation of IL34, which is associated with poor survival, and with alterations in LC spatial organisation and function. These findings suggest that reduced IL34 expression in SCC may contribute to impaired local immunity through LC dysregulation.
{"title":"Squamous cell carcinoma is associated with reduced IL34 expression, alterations in the Langerhans cell antigen-processing-presentation machinery and poor patient survival","authors":"Thi Viet Trinh Dang, Kevin R Gillinder, Quan Nguyen, Onkar Mulay, Tuan Vo, Ahmed M Mehdi, Chenhao Zhou, Andrew J Brooks, Graham R Leggatt, David A Hume, Ian H Frazer, Janin Chandra","doi":"10.1002/cti2.70018","DOIUrl":"https://doi.org/10.1002/cti2.70018","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Langerhans cells (LCs) are epithelial antigen-presenting cells (APC) contributing to immune surveillance. LCs depend on interleukin 34 (IL34) production by epithelial cells. This study aimed to uncover mechanisms of alteration of IL34 and LC function in squamous cell carcinoma (SCC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Cancer cohort data were used to identify associations between SCC and IL34. ATAC-seq of keratinocytes (KCs) and LCs from a murine model of epithelial hyperplasia, driven by HPV16 E7 oncoprotein (K14E7), was analysed. Transcriptomic data were used to validate findings. RNAscope, RT-qPCR, ELISA and confocal imaging was used to analyse IL34 expression and LCs in a spatial context.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p><i>IL34</i> mRNA is downregulated in human SCCs of the head and neck, the cervix, the lung and the oesophagus, and low <i>IL34</i> expression is associated with poor survival. We demonstrate that KCs of K14E7 mice have reduced <i>Il34</i> gene accessibility, mRNA and protein, as well as broad changes in promotor accessibility associated with cell adhesion and immune responses. Chromatin accessibility was substantially changed in LCs, including increased accessibility of the <i>Csf1r</i> gene, and changes in promotors associated with cytoskeleton arrangement and antigen processing and presentation. We discovered altered spatial LC dendrite organisation in hyperproliferative epithelium.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Squamous cell carcinoma of the cervix, head and neck, oesophagus and lung demonstrate downregulation of IL34, which is associated with poor survival, and with alterations in LC spatial organisation and function. These findings suggest that reduced IL34 expression in SCC may contribute to impaired local immunity through LC dysregulation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 12","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The recent H5N1 avian influenza outbreak in the USA has sparked fresh fears of avian viruses causing the next pandemic. To date, the H5N1 (clade 2.3.4.4b) outbreak in cattle has spread across several states in the USA, with several humans infected following exposure to cows. This H5N1 clade is also reportedly circulating across Europe, Africa and South America. H5N1 was also detected in a child returning to Australia following travel in India where H5N1 (clade 2.3.2.1a) is also reported to be circulating. There are no licenced vaccines against H5N1 avian influenza viruses for humans. Current vaccines aim to protect against seasonal H1N1 and H3N2 variants are unlikely to provide much protection against the different H5, or other avian viruses. CD8+ T cells are known to provide protection against influenza infection, enhancing viral control and decreasing disease severity.
Methods
We recently compiled and published a list of the known immunogenic influenza-derived CD8+ T cell epitopes restricted to the most prevalent 10 HLA-A, -B and -C molecules worldwide. We assessed the conservation of a curated list of these influenza A virus-derived CD8+ T cell epitopes in H5N1 viruses' sequences at the heart of the outbreak.
Results
We identified that > 64% of the CD8+ T cell epitopes are highly conserved (> 90% sequence identity) in the H5N1 viruses, with 60% (18/30) of the most prevalent HLA-I molecules have at least one immunogenic CD8+ T cell epitope conserved in H5N1 viruses. Together these HLA-I molecules with conserved epitopes have a cumulative total of > 100% global coverage. Epitopes derived from the NP, M1, PB2, NS1 and PB1 proteins displayed the highest level of conservation.
Conclusions
Together, this analysis highlights that globally there is the potential for T cell cross-recognition against the H5N1 viruses that may provide some protection in humans towards the current avian flu outbreak.
{"title":"CD8+ T cell epitope conservation in emerging H5N1 viruses suggests global protection","authors":"Emma J Grant, Stephanie Gras","doi":"10.1002/cti2.70017","DOIUrl":"https://doi.org/10.1002/cti2.70017","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The recent H5N1 avian influenza outbreak in the USA has sparked fresh fears of avian viruses causing the next pandemic. To date, the H5N1 (clade 2.3.4.4b) outbreak in cattle has spread across several states in the USA, with several humans infected following exposure to cows. This H5N1 clade is also reportedly circulating across Europe, Africa and South America. H5N1 was also detected in a child returning to Australia following travel in India where H5N1 (clade 2.3.2.1a) is also reported to be circulating. There are no licenced vaccines against H5N1 avian influenza viruses for humans. Current vaccines aim to protect against seasonal H1N1 and H3N2 variants are unlikely to provide much protection against the different H5, or other avian viruses. CD8<sup>+</sup> T cells are known to provide protection against influenza infection, enhancing viral control and decreasing disease severity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We recently compiled and published a list of the known immunogenic influenza-derived CD8<sup>+</sup> T cell epitopes restricted to the most prevalent 10 HLA-A, -B and -C molecules worldwide. We assessed the conservation of a curated list of these influenza A virus-derived CD8<sup>+</sup> T cell epitopes in H5N1 viruses' sequences at the heart of the outbreak.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified that > 64% of the CD8<sup>+</sup> T cell epitopes are highly conserved (> 90% sequence identity) in the H5N1 viruses, with 60% (18/30) of the most prevalent HLA-I molecules have at least one immunogenic CD8<sup>+</sup> T cell epitope conserved in H5N1 viruses. Together these HLA-I molecules with conserved epitopes have a cumulative total of > 100% global coverage. Epitopes derived from the NP, M1, PB2, NS1 and PB1 proteins displayed the highest level of conservation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Together, this analysis highlights that globally there is the potential for T cell cross-recognition against the H5N1 viruses that may provide some protection in humans towards the current avian flu outbreak.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 11","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70017","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142707677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Susan N Christo, Keely M McDonald, Thomas N Burn, Nadia Kurd, Jessica Stanfield, Megan M Kaneda, Ruth Seelige, Christopher P Dillon, Timothy S Fisher, Bas Baaten, Laura K Mackay
Objectives
Bispecific antibodies targeting CD47 and PD-L1 (CD47 × PD-L1 BisAb) demonstrate efficacy against a range of solid cancers. While dual blockade negates anti-CD47-mediated toxicity, the effect of combined innate and adaptive immune activation on protective tumor-resident CD8+ T cells has yet to be fully elucidated.
Methods
CD8+ T cell populations were tracked upon CD47 × PD-L1 BisAb treatment in an orthotopic model of murine breast cancer where anti-tumor immunity is mediated by CD8+ T cells. Immune responses were also compared with anti-PD-L1 monotherapy to assess the advantage of dual checkpoint targeting.
Results
We found that CD47 × PD-L1 BisAb treatment augmented CD8+ T cell responses in tumors, which resulted in enhanced tumor control. Compared with anti-PD-L1 treatment, dual CD47 and PD-L1 blockade promoted greater numbers of antigen-specific tumor-resident CD8+ T cells that exhibited increased cytokine production.
Conclusions
Engagement of innate and adaptive immune checkpoint molecules via CD47 × PD-L1 BisAb treatment resulted in robust CD8+ T cell responses, including the induction of tumor-resident CD8+ T cells that exhibited functionally superior anti-tumor immunity. These results demonstrate that innate immune activation potentiates anti-tumor adaptive responses, highlighting the use of dual checkpoint blockade as an optimal strategy for promoting CD8+ T cell-mediated protection.
目的 针对 CD47 和 PD-L1 的双特异性抗体（CD47 × PD-L1 双抗体）对一系列实体瘤具有疗效。虽然双重阻断否定了抗 CD47 介导的毒性，但先天性免疫和适应性免疫联合激活对保护性肿瘤驻留 CD8+ T 细胞的影响尚未完全阐明。 方法 在 CD47 × PD-L1 BisAb 治疗小鼠乳腺癌的正位模型中，跟踪 CD8+ T 细胞群，该模型中的抗肿瘤免疫由 CD8+ T 细胞介导。免疫反应还与抗 PD-L1 单一疗法进行了比较，以评估双重检查点靶向的优势。 结果 我们发现，CD47 × PD-L1 BisAb 治疗增强了肿瘤中的 CD8+ T 细胞反应，从而提高了肿瘤控制率。与抗-PD-L1治疗相比，CD47和PD-L1双重阻断促进了更多的抗原特异性肿瘤驻留CD8+ T细胞，这些细胞产生的细胞因子也有所增加。 结论 通过 CD47 × PD-L1 BisAb 处理先天性和适应性免疫检查点分子的参与可产生强大的 CD8+ T 细胞反应，包括诱导肿瘤驻留的 CD8+ T 细胞，这些细胞表现出卓越的抗肿瘤免疫功能。这些结果表明，先天性免疫激活可增强抗肿瘤适应性反应，突出表明使用双重检查点阻断是促进 CD8+ T 细胞介导的保护的最佳策略。
{"title":"Dual CD47 and PD-L1 blockade elicits anti-tumor immunity by intratumoral CD8+ T cells","authors":"Susan N Christo, Keely M McDonald, Thomas N Burn, Nadia Kurd, Jessica Stanfield, Megan M Kaneda, Ruth Seelige, Christopher P Dillon, Timothy S Fisher, Bas Baaten, Laura K Mackay","doi":"10.1002/cti2.70014","DOIUrl":"https://doi.org/10.1002/cti2.70014","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Bispecific antibodies targeting CD47 and PD-L1 (CD47 × PD-L1 BisAb) demonstrate efficacy against a range of solid cancers. While dual blockade negates anti-CD47-mediated toxicity, the effect of combined innate and adaptive immune activation on protective tumor-resident CD8<sup>+</sup> T cells has yet to be fully elucidated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>CD8<sup>+</sup> T cell populations were tracked upon CD47 × PD-L1 BisAb treatment in an orthotopic model of murine breast cancer where anti-tumor immunity is mediated by CD8<sup>+</sup> T cells. Immune responses were also compared with anti-PD-L1 monotherapy to assess the advantage of dual checkpoint targeting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that CD47 × PD-L1 BisAb treatment augmented CD8<sup>+</sup> T cell responses in tumors, which resulted in enhanced tumor control. Compared with anti-PD-L1 treatment, dual CD47 and PD-L1 blockade promoted greater numbers of antigen-specific tumor-resident CD8<sup>+</sup> T cells that exhibited increased cytokine production.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Engagement of innate and adaptive immune checkpoint molecules via CD47 × PD-L1 BisAb treatment resulted in robust CD8<sup>+</sup> T cell responses, including the induction of tumor-resident CD8<sup>+</sup> T cells that exhibited functionally superior anti-tumor immunity. These results demonstrate that innate immune activation potentiates anti-tumor adaptive responses, highlighting the use of dual checkpoint blockade as an optimal strategy for promoting CD8<sup>+</sup> T cell-mediated protection.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 11","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142707678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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