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}
Dwarakanathan Ranganathan, Saskia Leibowitz, George T John, Michelle A Neller, George R Ambalathingal, Leone Beagley, Archana Panikkar, Shannon Best, Jyothy Raju, Hilary Reddiex, Sharad Ratanjee, Monica Suet Ying Ng, Corey Smith, Rajiv Khanna
Objectives
Dysregulation of Epstein–Barr virus (EBV)-specific cellular immunity has been hypothesised as one of the contributing factors in the pathogenesis of systemic lupus erythematosus (SLE). Lupus nephritis is a major risk factor for overall morbidity in SLE. Immune-based strategies directed to EBV have been proposed as potential therapeutic strategy for SLE and lupus nephritis.
Methods
Autologous EBV latent antigen-specific CD4+ and CD8+ T cells were expanded in vitro and adoptively transferred to a lupus nephritis patient.
Results
This adoptive immunotherapy had no immediate adverse effects, and the patient was subsequently treated with the anti-CD20 antibody, obinutuzumab. The patient showed a reduction in anti-dsDNA antibodies and improved glomerular filtration rate but remained nephrotic. These observations were coincident with a reduction in anti-viral and global T-cell activation.
Conclusion
To our knowledge, this is the first report of the use of EBV-specific adoptive immunotherapy to treat a patient with lupus nephritis.
目的：爱泼斯坦-巴氏病毒（EBV）特异性细胞免疫失调被认为是系统性红斑狼疮（SLE）发病机制的诱因之一。狼疮性肾炎是系统性红斑狼疮总体发病率的主要风险因素。针对EB病毒的免疫策略已被提出作为系统性红斑狼疮和狼疮性肾炎的潜在治疗策略：方法：在体外扩增自体EB病毒潜伏抗原特异性CD4+和CD8+T细胞，并将其收养性转移给狼疮肾炎患者：结果：这种采纳性免疫疗法没有立即产生不良反应，患者随后接受了抗CD20抗体--奥比妥珠单抗的治疗。患者体内的抗dsDNA抗体有所减少，肾小球滤过率也有所改善，但仍然存在肾病。这些观察结果与抗病毒和整体 T 细胞活化的减少相吻合：据我们所知，这是首次报道使用 EBV 特异性免疫疗法治疗狼疮肾炎患者。
{"title":"Autologous Epstein–Barr virus-specific adoptive T-cell therapy in a patient with lupus nephritis","authors":"Dwarakanathan Ranganathan, Saskia Leibowitz, George T John, Michelle A Neller, George R Ambalathingal, Leone Beagley, Archana Panikkar, Shannon Best, Jyothy Raju, Hilary Reddiex, Sharad Ratanjee, Monica Suet Ying Ng, Corey Smith, Rajiv Khanna","doi":"10.1002/cti2.70015","DOIUrl":"10.1002/cti2.70015","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Dysregulation of Epstein–Barr virus (EBV)-specific cellular immunity has been hypothesised as one of the contributing factors in the pathogenesis of systemic lupus erythematosus (SLE). Lupus nephritis is a major risk factor for overall morbidity in SLE. Immune-based strategies directed to EBV have been proposed as potential therapeutic strategy for SLE and lupus nephritis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Autologous EBV latent antigen-specific CD4<sup>+</sup> and CD8<sup>+</sup> T cells were expanded <i>in vitro</i> and adoptively transferred to a lupus nephritis patient.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>This adoptive immunotherapy had no immediate adverse effects, and the patient was subsequently treated with the anti-CD20 antibody, obinutuzumab. The patient showed a reduction in anti-dsDNA antibodies and improved glomerular filtration rate but remained nephrotic. These observations were coincident with a reduction in anti-viral and global T-cell activation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>To our knowledge, this is the first report of the use of EBV-specific adoptive immunotherapy to treat a patient with lupus nephritis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 11","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674667","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}
C-reactive protein (CRP) is a well-known acute-phase protein that increases remarkably under various inflammatory conditions and is elevated in patients with malignant tumors. In this study, we investigated the influence of CRP on the tumor microenvironment in clear cell renal cell carcinoma (ccRCC).
Methods
This study explored CRP's role in ccRCC by co-culturing human macrophages with ccRCC cells and employing antibody blocking, RNA sequencing and in vitro experiments for functional insights. We also analysed The Cancer Genome Atlas Program (TCGA) data to link CD64 expression with ccRCC prognosis and used immunohistochemistry to associate CD64+ macrophages with tumor severity and systemic CRP levels.
Results
A co-culture study using human macrophages and RCC cell lines showed that CRP-stimulated macrophages secrete IL-6, which induces RCC proliferation via STAT3 activation. CRP-induced protumor activation of macrophages was suppressed by CD64 blocking antibodies. Furthermore, CRP elevates PD-L1 expression in macrophages via the CD64-STAT1 signalling pathway. Statistical analysis of TCGA data indicated that increased CD64 expression was associated with a worse clinical course in ccRCC. Immunohistochemical analysis of pathological specimens revealed that high CD64 expression in tumor-associated macrophages (TAMs), and a high density of CD64+ TAMs, was linked to high nuclear grade and stage. High CD64 expression was also correlated with increased serum CRP levels.
Conclusions
The CRP-CD64 signal was linked to the protumor activation of TAMs and could be a promising target for anticancer immunotherapy in ccRCC.
{"title":"The contribution of the CRP/CD64 axis to renal cancer progression by inducing protumor activation of tumor-associated macrophages","authors":"Cheng Pan, Yukio Fujiwara, Hiromu Yano, Toshiki Anami, Yuki Ibe, Lianbo Li, Yuji Miura, Takanobu Motoshima, Shigeyuki Esumi, Junji Yatsuda, Taizo Hibi, Tomomi Kamba, Yoshihiro Komohara","doi":"10.1002/cti2.70013","DOIUrl":"10.1002/cti2.70013","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>C-reactive protein (CRP) is a well-known acute-phase protein that increases remarkably under various inflammatory conditions and is elevated in patients with malignant tumors. In this study, we investigated the influence of CRP on the tumor microenvironment in clear cell renal cell carcinoma (ccRCC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study explored CRP's role in ccRCC by co-culturing human macrophages with ccRCC cells and employing antibody blocking, RNA sequencing and <i>in vitro</i> experiments for functional insights. We also analysed The Cancer Genome Atlas Program (TCGA) data to link CD64 expression with ccRCC prognosis and used immunohistochemistry to associate CD64<sup>+</sup> macrophages with tumor severity and systemic CRP levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A co-culture study using human macrophages and RCC cell lines showed that CRP-stimulated macrophages secrete IL-6, which induces RCC proliferation via STAT3 activation. CRP-induced protumor activation of macrophages was suppressed by CD64 blocking antibodies. Furthermore, CRP elevates PD-L1 expression in macrophages via the CD64-STAT1 signalling pathway. Statistical analysis of TCGA data indicated that increased CD64 expression was associated with a worse clinical course in ccRCC. Immunohistochemical analysis of pathological specimens revealed that high CD64 expression in tumor-associated macrophages (TAMs), and a high density of CD64<sup>+</sup> TAMs, was linked to high nuclear grade and stage. High CD64 expression was also correlated with increased serum CRP levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The CRP-CD64 signal was linked to the protumor activation of TAMs and could be a promising target for anticancer immunotherapy in ccRCC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 11","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674669","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}
Stephen Tukwasibwe, Savannah Nicole Lewis, Yoweri Taremwa, Kattria van der Ploeg, Kathleen D Press, Maureen Ty, Felistas Namirimu Nankya, Kenneth Musinguzi, Evelyn Nansubuga, Florian Bach, Martin Chamai, Martin Okitwi, Gerald Tumusiime, Annettee Nakimuli, Francesco Colucci, Moses R Kamya, Joaniter I Nankabirwa, Emmanuel Arinaitwe, Bryan Greenhouse, Grant Dorsey, Philip J Rosenthal, Isaac Ssewanyana, Prasanna Jagannathan
Objectives
Natural killer (NK) cells make important contributions to anti-malarial immunity through antibody-dependent cellular cytotoxicity (ADCC), but the role of different components of this pathway in promoting NK cell activation remains unclear.
Methods
We compared the functions and phenotypes of NK cells from malaria-exposed and malaria-naive donors, and then varied the erythrocyte genetic background, Plasmodium falciparum strain and opsonising plasma used in ADCC to observe their impacts on NK cell degranulation as measured by CD107a mobilisation.
Results
Natural killer cells from malaria-exposed adult Ugandan donors had enhanced ADCC, but an impaired pro-inflammatory response to cytokine stimulation, compared to NK cells obtained from malaria-naive adult North American donors. Cellular phenotypes from malaria-exposed donors reflected this specialisation for ADCC, with a compartment-wide downregulation of the Fc receptor γ-chain and enrichment of highly differentiated CD56dim and CD56neg populations. NK cell degranulation was enhanced in response to opsonised P. falciparum schizonts cultured in sickle cell heterozygous erythrocytes relative to wild-type erythrocytes, and when using opsonising plasma collected from donors living in a high transmission area compared to a lower transmission area despite similar levels of 3D7 schizont-specific IgG levels. However, degranulation was lowered in response to opsonised field isolate P. falciparum schizonts isolated from clinical malaria infections, compared to the 3D7 laboratory strain typically used in these assays.
Conclusion
This work highlights important host and parasite factors that contribute to ADCC efficacy that should be considered in the design of ADCC assays.
目的 自然杀伤（NK）细胞通过抗体依赖性细胞毒性（ADCC）对抗疟免疫做出了重要贡献，但这一途径的不同成分在促进 NK 细胞活化方面的作用仍不清楚。 方法 我们比较了来自疟疾暴露供体和疟疾免疫供体的 NK 细胞的功能和表型，然后改变了 ADCC 中使用的红细胞遗传背景、恶性疟原虫菌株和疏松血浆，以观察它们对 NK 细胞脱颗粒的影响（通过 CD107a 动员测量）。 结果 与来自对疟疾免疫的北美成年供体的 NK 细胞相比，来自疟疾暴露的乌干达成年供体的自然杀伤细胞的 ADCC 增强，但对细胞因子刺激的促炎反应减弱。疟疾暴露供体的细胞表型反映了这种ADCC特化，Fc受体γ-链在整个区段范围内下调，高度分化的CD56dim和CD56neg种群富集。与野生型红细胞相比，在镰状细胞杂合子红细胞中培养的恶性疟原虫裂殖体的疏松化过程中，NK细胞的脱颗粒反应增强；尽管3D7裂殖体特异性IgG水平相似，但与低传播地区相比，当使用从高传播地区捐献者处收集的疏松化血浆时，NK细胞的脱颗粒反应也增强。然而，与这些试验中通常使用的 3D7 实验室菌株相比，对从临床疟疾感染中分离出来的野外分离的恶性疟原虫裂殖体的去颗粒化反应较低。 结论 这项工作强调了促进 ADCC 效能的重要宿主和寄生虫因素，在设计 ADCC 试验时应考虑到这些因素。
{"title":"Natural killer cell antibody-dependent cellular cytotoxicity to Plasmodium falciparum is impacted by cellular phenotypes, erythrocyte polymorphisms, parasite diversity and intensity of transmission","authors":"Stephen Tukwasibwe, Savannah Nicole Lewis, Yoweri Taremwa, Kattria van der Ploeg, Kathleen D Press, Maureen Ty, Felistas Namirimu Nankya, Kenneth Musinguzi, Evelyn Nansubuga, Florian Bach, Martin Chamai, Martin Okitwi, Gerald Tumusiime, Annettee Nakimuli, Francesco Colucci, Moses R Kamya, Joaniter I Nankabirwa, Emmanuel Arinaitwe, Bryan Greenhouse, Grant Dorsey, Philip J Rosenthal, Isaac Ssewanyana, Prasanna Jagannathan","doi":"10.1002/cti2.70005","DOIUrl":"https://doi.org/10.1002/cti2.70005","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Natural killer (NK) cells make important contributions to anti-malarial immunity through antibody-dependent cellular cytotoxicity (ADCC), but the role of different components of this pathway in promoting NK cell activation remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We compared the functions and phenotypes of NK cells from malaria-exposed and malaria-naive donors, and then varied the erythrocyte genetic background, <i>Plasmodium falciparum</i> strain and opsonising plasma used in ADCC to observe their impacts on NK cell degranulation as measured by CD107a mobilisation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Natural killer cells from malaria-exposed adult Ugandan donors had enhanced ADCC, but an impaired pro-inflammatory response to cytokine stimulation, compared to NK cells obtained from malaria-naive adult North American donors. Cellular phenotypes from malaria-exposed donors reflected this specialisation for ADCC, with a compartment-wide downregulation of the Fc receptor γ-chain and enrichment of highly differentiated CD56<sup>dim</sup> and CD56<sup>neg</sup> populations. NK cell degranulation was enhanced in response to opsonised <i>P. falciparum</i> schizonts cultured in sickle cell heterozygous erythrocytes relative to wild-type erythrocytes, and when using opsonising plasma collected from donors living in a high transmission area compared to a lower transmission area despite similar levels of 3D7 schizont-specific IgG levels. However, degranulation was lowered in response to opsonised field isolate <i>P. falciparum</i> schizonts isolated from clinical malaria infections, compared to the 3D7 laboratory strain typically used in these assays.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This work highlights important host and parasite factors that contribute to ADCC efficacy that should be considered in the design of ADCC assays.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 11","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142561635","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}
Giuseppe Ercoli, Hugh Selway-Clarke, Dena Truijen, Milda Folkmanaite, Tate Oulton, Caitlin Norris-Grey, Rie Nakajima, Philip Felgner, Brendan W Wren, Kevin Tetteh, Nicholas J Croucher, Maria Leandro, Geraldine Cambridge, Jeremy S Brown
Objectives
Patients with rheumatoid arthritis (RA) have an increased susceptibility to infections, including those caused by Streptococcus pneumoniae. Why RA is associated with increased susceptibility to S. pneumoniae is poorly understood. This study aims to assess the effects of RA and B-cell depletion therapy on naturally acquired antibody responses to 289 S. pneumoniae protein antigens using a novel protein array.
Methods
IgG responses to S. pneumoniae were characterised in serum from RA patients and disease controls (myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)) using whole-cell ELISA, a flow cytometry opsonisation assay and an S. pneumoniae protein array. For the RA patients, results were compared before and after B-cell depletion therapy.
Results
Compared to a well-characterised disease control group of ME/CFS patients, RA patients had reduced antibody responses to multiple S. pneumoniae protein antigens, with significant IgG recognition of approximately half the number of antigens along with reduced median strengths of these responses. Reduction in multiple array antigen-specific responses also correlated with reduced IgG opsonisation of S. pneumoniae. Although B-cell depletion therapy with rituximab did not reduce overall IgG recognition of S. pneumoniae in the RA group, it was associated with marked disruption of pre-existing IgG repertoire to protein antigens in individual patients.
Conclusion
These data show RA is associated with major disruption of naturally acquired adaptive immunity to S. pneumoniae, which can be assessed rapidly using a protein antigen array and is likely to contribute towards the increased incidence of pneumonia in patients with RA.
目的 类风湿性关节炎（RA）患者对感染的易感性增加，其中包括由肺炎链球菌引起的感染。目前尚不清楚 RA 为什么会增加对肺炎链球菌的易感性。本研究旨在使用新型蛋白质阵列评估 RA 和 B 细胞耗竭疗法对 289 种肺炎链球菌蛋白质抗原的天然抗体反应的影响。 方法 采用全细胞酶联免疫吸附试验、流式细胞仪抗溶血试验和肺炎双球菌蛋白阵列分析 RA 患者和疾病对照组（肌痛性脑脊髓炎/慢性疲劳综合征（ME/CFS））血清中肺炎双球菌 IgG 反应的特征。对 RA 患者进行了 B 细胞耗竭治疗前后的结果比较。 结果 与特征明确的疾病对照组 ME/CFS 患者相比，RA 患者对多种肺炎双球菌蛋白抗原的抗体反应减弱，对大约一半抗原的 IgG 识别率明显下降，同时这些反应的中位强度也有所降低。多种阵列抗原特异性反应的降低还与肺炎双球菌的IgG蛋白溶解度降低有关。虽然使用利妥昔单抗的 B 细胞耗竭疗法并未降低 RA 组对肺炎双球菌的总体 IgG 识别率，但却明显破坏了个别患者对蛋白质抗原的原有 IgG 反应谱系。 结论 这些数据表明，RA 与对肺炎双球菌的自然获得性适应性免疫的严重破坏有关，这种破坏可通过蛋白抗原阵列进行快速评估，并可能导致 RA 患者肺炎发病率的增加。
{"title":"Naturally acquired adaptive immunity to Streptococcus pneumoniae is impaired in rheumatoid arthritis patients","authors":"Giuseppe Ercoli, Hugh Selway-Clarke, Dena Truijen, Milda Folkmanaite, Tate Oulton, Caitlin Norris-Grey, Rie Nakajima, Philip Felgner, Brendan W Wren, Kevin Tetteh, Nicholas J Croucher, Maria Leandro, Geraldine Cambridge, Jeremy S Brown","doi":"10.1002/cti2.70012","DOIUrl":"https://doi.org/10.1002/cti2.70012","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Patients with rheumatoid arthritis (RA) have an increased susceptibility to infections, including those caused by <i>Streptococcus pneumoniae</i>. Why RA is associated with increased susceptibility to <i>S. pneumoniae</i> is poorly understood. This study aims to assess the effects of RA and B-cell depletion therapy on naturally acquired antibody responses to 289 <i>S. pneumoniae</i> protein antigens using a novel protein array.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>IgG responses to <i>S. pneumoniae</i> were characterised in serum from RA patients and disease controls (myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)) using whole-cell ELISA, a flow cytometry opsonisation assay and an <i>S. pneumoniae</i> protein array. For the RA patients, results were compared before and after B-cell depletion therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared to a well-characterised disease control group of ME/CFS patients, RA patients had reduced antibody responses to multiple <i>S. pneumoniae</i> protein antigens, with significant IgG recognition of approximately half the number of antigens along with reduced median strengths of these responses. Reduction in multiple array antigen-specific responses also correlated with reduced IgG opsonisation of <i>S. pneumoniae</i>. Although B-cell depletion therapy with rituximab did not reduce overall IgG recognition of <i>S. pneumoniae</i> in the RA group, it was associated with marked disruption of pre-existing IgG repertoire to protein antigens in individual patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These data show RA is associated with major disruption of naturally acquired adaptive immunity to <i>S. pneumoniae</i>, which can be assessed rapidly using a protein antigen array and is likely to contribute towards the increased incidence of pneumonia in patients with RA.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 10","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443415","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}
Wenlin Qiu, Xiaoxiao Han, Tong Yu, Lijuan Jiang, Xuefei Wang, Ruizhi Feng, Xiaoru Duan, Yao Teng, Haifeng Yin, Maria I Bokarewa, Guo-Min Deng
Objectives
Systemic lupus erythematosus (SLE) is a chronic and severe autoimmune disease characterised by persistent inflammation. Hydroxychloroquine (HCQ) and glucocorticoids (GCs) are the primary agents commonly used in combination as the first-line treatment for SLE. Nevertheless, the specific mechanisms responsible for the effectiveness of this combined therapy with HCQ and GCs have not been fully elucidated. This study aimed to reveal the mechanism behind combined HCQ and GC treatment in lupus.
Methods
An SLE IgG-induced inflammation model was used to investigate the anti-inflammatory effects of HCQ and dexamethasone (DXM). A glucocorticoid-induced osteoporosis (GIOP) model was used to investigate the inhibitory effect of HCQ on osteoclastogenesis. Inflammation was assessed by haematoxylin and eosin staining. Bone metabolism was determined structurally via microcomputer tomography and in bone marrow-derived osteoclast cultures.
Results
An SLE IgG-induced inflammation model demonstrated that HCQ could not ameliorate inflammation alone but could enhance the anti-inflammatory effect of GCs by decreasing the expression of FcγRI on macrophages. HCQ inhibited osteoclastogenesis induced by GCs and RANKL by upregulating nuclear factor erythroid 2-related factor 2 and limiting reactive oxygen species formation, which mitigated GC-induced bone loss.
Conclusion
The results indicate that HCQ improved the anti-inflammatory effects of GCs and inhibits the osteoclastogenesis in experimental lupus. This study offers valuable insights into the mechanisms underlying the combined treatment of lupus with HCQ and GCs.
{"title":"Inhibitory effect of hydroxychloroquine on glucocorticoid-induced osteoporosis in lupus therapy","authors":"Wenlin Qiu, Xiaoxiao Han, Tong Yu, Lijuan Jiang, Xuefei Wang, Ruizhi Feng, Xiaoru Duan, Yao Teng, Haifeng Yin, Maria I Bokarewa, Guo-Min Deng","doi":"10.1002/cti2.70010","DOIUrl":"https://doi.org/10.1002/cti2.70010","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Systemic lupus erythematosus (SLE) is a chronic and severe autoimmune disease characterised by persistent inflammation. Hydroxychloroquine (HCQ) and glucocorticoids (GCs) are the primary agents commonly used in combination as the first-line treatment for SLE. Nevertheless, the specific mechanisms responsible for the effectiveness of this combined therapy with HCQ and GCs have not been fully elucidated. This study aimed to reveal the mechanism behind combined HCQ and GC treatment in lupus.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>An SLE IgG-induced inflammation model was used to investigate the anti-inflammatory effects of HCQ and dexamethasone (DXM). A glucocorticoid-induced osteoporosis (GIOP) model was used to investigate the inhibitory effect of HCQ on osteoclastogenesis. Inflammation was assessed by haematoxylin and eosin staining. Bone metabolism was determined structurally via microcomputer tomography and in bone marrow-derived osteoclast cultures.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>An SLE IgG-induced inflammation model demonstrated that HCQ could not ameliorate inflammation alone but could enhance the anti-inflammatory effect of GCs by decreasing the expression of FcγRI on macrophages. HCQ inhibited osteoclastogenesis induced by GCs and RANKL by upregulating nuclear factor erythroid 2-related factor 2 and limiting reactive oxygen species formation, which mitigated GC-induced bone loss.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The results indicate that HCQ improved the anti-inflammatory effects of GCs and inhibits the osteoclastogenesis in experimental lupus. This study offers valuable insights into the mechanisms underlying the combined treatment of lupus with HCQ and GCs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 10","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142435410","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}
Lymphocyte activation gene 3 (LAG3), an inhibitory receptor in T-cell activation, is a negative prognostic factor. However, its impact on tumours has yet to be comprehensively elucidated on a pan-cancer scale. Thus, we aim to reveal its role at the pan-cancer level.
Methods
We performed IHC staining on a retrospective cohort of 370 patients. Then we assessed the prognostic effect of LAG3 using Kaplan–Meier survival analysis and multivariate Cox regression analysis. In pan-cancer analysis, we constructed competing endogenous RNA and protein–protein interaction networks, conducted gene set enrichment analysis and identified correlations between LAG3 gene expression and various factors, including clinical characteristics, tumour purity, mutations, tumour immunity and drug sensitivity across 33 cancer types.
Results
LAG3 was expressed higher in normal kidney tissues than in tumours. A high level of LAG3 gene expression was an independent prognostic factor for OS (HR = 6.60, 95% CI = 2.43–17.90, P < 0.001) and PFS (HR = 3.44, 95% CI = 1.68–7.10, P < 0.001). In pan-cancer analysis, LAG3 exhibited robust correlations with survival and tumour stages in various cancers. Moreover, LAG3 was strongly associated with immune-related genes, proteins and signalling pathways. LAG3 gene expression was positively associated with increased infiltration of activated immune cells and decreased infiltration of several resting cells. LAG3 gene expression was associated with tumour mutation burden and microsatellite instability in multiple cancers.
Conclusion
High LAG3 gene expression was an independent risk factor in kidney neoplasms. It also functioned as a biomarker for prognosis, TIME and immunotherapy efficacy in the pan-cancer dimension.
研究目的淋巴细胞活化基因 3（LAG3）是 T 细胞活化过程中的一个抑制受体，是一个不利的预后因素。然而，它对肿瘤的影响尚未在泛癌症范围内得到全面阐明。因此，我们旨在揭示它在泛癌症中的作用：方法：我们对 370 例患者的回顾性队列进行了 IHC 染色。方法：我们对 370 例回顾性患者进行了 IHC 染色，然后使用 Kaplan-Meier 生存分析和多变量 Cox 回归分析评估了 LAG3 的预后作用。在泛癌症分析中，我们构建了竞争内源性RNA和蛋白-蛋白相互作用网络，进行了基因组富集分析，并确定了33种癌症类型中LAG3基因表达与临床特征、肿瘤纯度、突变、肿瘤免疫和药物敏感性等各种因素之间的相关性：结果：LAG3在正常肾组织中的表达高于肿瘤。LAG3基因高表达是OS的独立预后因素（HR = 6.60，95% CI = 2.43-17.90, P P 结论：LAG3基因高表达是OS的独立预后因素：LAG3基因高表达是肾脏肿瘤的一个独立危险因素。在泛癌症维度上，它还是预后、TIME和免疫疗法疗效的生物标志物。
{"title":"Lymphocyte activation gene 3 served as a potential prognostic and immunological biomarker across various cancer types: a clinical and pan-cancer analysis","authors":"Yifan Liu, Yuntao Yao, Xinyue Yang, Maodong Wei, Bingnan Lu, Keqing Dong, Donghao Lyu, Yuanan Li, Wenbin Guan, Runzhi Huang, Guofeng Xu, Xiuwu Pan","doi":"10.1002/cti2.70009","DOIUrl":"10.1002/cti2.70009","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Lymphocyte activation gene 3 (LAG3), an inhibitory receptor in T-cell activation, is a negative prognostic factor. However, its impact on tumours has yet to be comprehensively elucidated on a pan-cancer scale. Thus, we aim to reveal its role at the pan-cancer level.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed IHC staining on a retrospective cohort of 370 patients. Then we assessed the prognostic effect of LAG3 using Kaplan–Meier survival analysis and multivariate Cox regression analysis. In pan-cancer analysis, we constructed competing endogenous RNA and protein–protein interaction networks, conducted gene set enrichment analysis and identified correlations between LAG3 gene expression and various factors, including clinical characteristics, tumour purity, mutations, tumour immunity and drug sensitivity across 33 cancer types.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>LAG3 was expressed higher in normal kidney tissues than in tumours. A high level of LAG3 gene expression was an independent prognostic factor for OS (HR = 6.60, 95% CI = 2.43–17.90, <i>P</i> < 0.001) and PFS (HR = 3.44, 95% CI = 1.68–7.10, <i>P</i> < 0.001). In pan-cancer analysis, LAG3 exhibited robust correlations with survival and tumour stages in various cancers. Moreover, LAG3 was strongly associated with immune-related genes, proteins and signalling pathways. LAG3 gene expression was positively associated with increased infiltration of activated immune cells and decreased infiltration of several resting cells. LAG3 gene expression was associated with tumour mutation burden and microsatellite instability in multiple cancers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>High LAG3 gene expression was an independent risk factor in kidney neoplasms. It also functioned as a biomarker for prognosis, TIME and immunotherapy efficacy in the pan-cancer dimension.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 10","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379659","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}
Kathrin Kläsener, Nadja Herrmann, Liliana Håversen, Timothy Sundell, Martina Sundqvist, Christina Lundqvist, Paul T Manna, Charlotte A Jonsson, Marcella Visentini, Diana Ljung Sass, Sarah McGrath, Kristoffer Grimstad, Alaitz Aranburu, Karin Mellgren, Linda Fogelstrand, Huamei Forsman, Olov Ekwall, Jan Borén, Inger Gjertsson, Michael Reth, Inga-Lill Mårtensson, Alessandro Camponeschi
Objectives
Paediatric Burkitt's lymphoma (pBL) is the most common childhood non-Hodgkin B-cell lymphoma. Despite the encouraging survival rates for most children, treating cases with relapse/resistance to current therapies remains challenging. CD38 is a transmembrane protein highly expressed in pBL. This study investigates the effectiveness of CD38-targeting monoclonal antibodies (mAbs), daratumumab and isatuximab, in impairing crucial cellular processes and survival pathways in pBL malignant cells.
Methods
In silico analyses of patient samples, combined with in vitro experiments using the Ramos cell line, were conducted to assess the impact of daratumumab and isatuximab on cellular proliferation, apoptosis and the phosphoinositide 3-kinase (PI3K) pathway.
Results
Isatuximab was found to be more effective than daratumumab in disrupting B-cell receptor signalling, reducing cellular proliferation and inducing apoptosis. Additionally, isatuximab caused a significant impairment of the PI3K pathway and induced metabolic reprogramming in pBL cells. The study also revealed a correlation between CD38 and MYC expression levels in pBL patient samples, suggesting CD38 involvement in key oncogenic processes.
Conclusion
The study emphasises the therapeutic potential of CD38-targeting mAbs, particularly isatuximab, in pBL.
{"title":"Targeting CD38 with monoclonal antibodies disrupts key survival pathways in paediatric Burkitt's lymphoma malignant B cells","authors":"Kathrin Kläsener, Nadja Herrmann, Liliana Håversen, Timothy Sundell, Martina Sundqvist, Christina Lundqvist, Paul T Manna, Charlotte A Jonsson, Marcella Visentini, Diana Ljung Sass, Sarah McGrath, Kristoffer Grimstad, Alaitz Aranburu, Karin Mellgren, Linda Fogelstrand, Huamei Forsman, Olov Ekwall, Jan Borén, Inger Gjertsson, Michael Reth, Inga-Lill Mårtensson, Alessandro Camponeschi","doi":"10.1002/cti2.70011","DOIUrl":"10.1002/cti2.70011","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Paediatric Burkitt's lymphoma (pBL) is the most common childhood non-Hodgkin B-cell lymphoma. Despite the encouraging survival rates for most children, treating cases with relapse/resistance to current therapies remains challenging. CD38 is a transmembrane protein highly expressed in pBL. This study investigates the effectiveness of CD38-targeting monoclonal antibodies (mAbs), daratumumab and isatuximab, in impairing crucial cellular processes and survival pathways in pBL malignant cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p><i>In silico</i> analyses of patient samples, combined with <i>in vitro</i> experiments using the Ramos cell line, were conducted to assess the impact of daratumumab and isatuximab on cellular proliferation, apoptosis and the phosphoinositide 3-kinase (PI3K) pathway.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Isatuximab was found to be more effective than daratumumab in disrupting B-cell receptor signalling, reducing cellular proliferation and inducing apoptosis. Additionally, isatuximab caused a significant impairment of the PI3K pathway and induced metabolic reprogramming in pBL cells. The study also revealed a correlation between CD38 and MYC expression levels in pBL patient samples, suggesting CD38 involvement in key oncogenic processes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The study emphasises the therapeutic potential of CD38-targeting mAbs, particularly isatuximab, in pBL.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 10","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370396","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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