CD4+ T cell helper and regulatory function in human cancers has been well characterised. However, the definition of tumor-infiltrating CD4+ T cell exhaustion and how it contributes to the immune response and disease progression in human gastric cancer (GC) remain largely unknown.
Methods
A total of 128 GC patients were enrolled in the study. The expression of CD39 and PD-1 on CD4+ T cells in the different samples was analysed by flow cytometry. GC-infiltrating CD4+ T cell subpopulations based on CD39 expression were phenotypically and functionally assessed. The role of CD39 in the immune response of GC-infiltrating T cells was investigated by inhibiting CD39 enzymatic activity.
Results
In comparison with CD4+ T cells from the non-tumor tissues, significantly more GC-infiltrating CD4+ T cells expressed CD39. Most GC-infiltrating CD39+CD4+ T cells exhibited CD45RA−CCR7− effector–memory phenotype expressing more exhaustion-associated inhibitory molecules and transcription factors and produced less TNF-α, IFN-γ and cytolytic molecules than their CD39−CD4+ counterparts. Moreover, ex vivo inhibition of CD39 enzymatic activity enhanced their functional potential reflected by TNF-α and IFN-γ production. Finally, increased percentages of GC-infiltrating CD39+CD4+ T cells were positively associated with disease progression and patients' poorer overall survival.
Conclusion
Our study demonstrates that CD39 expression defines GC-infiltrating CD4+ T cell exhaustion and their immunosuppressive function. Targeting CD39 may be a promising therapeutic strategy for treating GC patients.
目标 CD4+ T 细胞在人类癌症中的辅助和调节功能已得到很好的描述。然而，肿瘤浸润性 CD4+ T 细胞衰竭的定义以及它如何导致人类胃癌（GC）的免疫反应和疾病进展在很大程度上仍是未知数。 方法 本研究共纳入了 128 例胃癌患者。流式细胞术分析了不同样本中 CD4+ T 细胞上 CD39 和 PD-1 的表达。根据 CD39 表达对 GC 浸润 CD4+ T 细胞亚群进行了表型和功能评估。通过抑制 CD39 酶的活性，研究了 CD39 在 GC 浸润 T 细胞免疫反应中的作用。 结果 与来自非肿瘤组织的 CD4+ T 细胞相比，表达 CD39 的 GC 浸润 CD4+ T 细胞明显增多。大多数GC浸润的CD39+CD4+ T细胞表现出CD45RA-CCR7-效应记忆表型，表达更多衰竭相关抑制分子和转录因子，产生的TNF-α、IFN-γ和细胞溶解分子少于CD39-CD4+同类细胞。此外，体内抑制 CD39 酶活性可提高它们的功能潜力，这体现在 TNF-α 和 IFN-γ 的产生上。最后，GC 浸润 CD39+CD4+ T 细胞百分比的增加与疾病进展和患者较差的总生存率呈正相关。 结论 我们的研究表明，CD39 的表达决定了 GC 浸润 CD4+ T 细胞的衰竭及其免疫抑制功能。以 CD39 为靶点可能是治疗 GC 患者的一种有前途的治疗策略。
{"title":"CD39 expression defines exhausted CD4+ T cells associated with poor survival and immune evasion in human gastric cancer","authors":"Zhen-quan Duan, Yu-xian Li, Yuan Qiu, Yang Shen, Ying Wang, Yuan-yuan Zhang, Bao-hang Zhu, Xiao-hong Yu, Xue-ling Tan, Weisan Chen, Yuan Zhuang, Ping Cheng, Wei-jun Zhang, Quan-ming Zou, Dai-yuan Ma, Liu-sheng Peng","doi":"10.1002/cti2.1499","DOIUrl":"https://doi.org/10.1002/cti2.1499","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>CD4<sup>+</sup> T cell helper and regulatory function in human cancers has been well characterised. However, the definition of tumor-infiltrating CD4<sup>+</sup> T cell exhaustion and how it contributes to the immune response and disease progression in human gastric cancer (GC) remain largely unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A total of 128 GC patients were enrolled in the study. The expression of CD39 and PD-1 on CD4<sup>+</sup> T cells in the different samples was analysed by flow cytometry. GC-infiltrating CD4<sup>+</sup> T cell subpopulations based on CD39 expression were phenotypically and functionally assessed. The role of CD39 in the immune response of GC-infiltrating T cells was investigated by inhibiting CD39 enzymatic activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In comparison with CD4<sup>+</sup> T cells from the non-tumor tissues, significantly more GC-infiltrating CD4<sup>+</sup> T cells expressed CD39. Most GC-infiltrating CD39<sup>+</sup>CD4<sup>+</sup> T cells exhibited CD45RA<sup>−</sup>CCR7<sup>−</sup> effector–memory phenotype expressing more exhaustion-associated inhibitory molecules and transcription factors and produced less TNF-α, IFN-γ and cytolytic molecules than their CD39<sup>−</sup>CD4<sup>+</sup> counterparts. Moreover, <i>ex vivo</i> inhibition of CD39 enzymatic activity enhanced their functional potential reflected by TNF-α and IFN-γ production. Finally, increased percentages of GC-infiltrating CD39<sup>+</sup>CD4<sup>+</sup> T cells were positively associated with disease progression and patients' poorer overall survival.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study demonstrates that CD39 expression defines GC-infiltrating CD4<sup>+</sup> T cell exhaustion and their immunosuppressive function. Targeting CD39 may be a promising therapeutic strategy for treating GC patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1499","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140145681","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}
Chloe Sligar, Ellie Reilly, Peter Cuthbertson, Kara L Vine, Katrina M Bird, Amal Elhage, Stephen I Alexander, Ronald Sluyter, Debbie Watson
Objectives
Donor haematopoietic stem cell transplantation treats leukaemia by inducing graft-versus-leukaemia (GVL) immunity. However, this benefit is often mitigated by graft-versus-host disease (GVHD), which is reduced by post-transplant cyclophosphamide (PTCy) alone or combined with tocilizumab (TOC) in humanised mice. This study established a preclinical humanised mouse model of GVL and investigated whether PTCy alone or combined with TOC impacts GVL immunity.
Methods
NOD-scid-IL2Rγnull mice were injected with 2 × 107 human peripheral blood mononuclear cells (hPBMCs) on day 0 and with 1 × 106 THP-1 acute myeloid leukaemia cells on day 14. In subsequent experiments, mice were also injected with PTCy (33 mg kg−1) or Dulbecco's phosphate buffered saline (PBS) on days 3 and 4, alone or combined with TOC or control antibody (25 mg kg−1) twice weekly for 28 days. Clinical signs of disease were monitored until day 42.
Results
Mice with hPBMCs from three different donors and THP-1 cells showed similar survival, clinical score and weight loss. hCD33+ leukaemia cells were minimal in mice reconstituted with hPBMCs from two donors but present in mice with hPBMCs from a third donor, suggesting donor-specific GVL responses. hPBMC-injected mice treated with PTCy alone or combined with TOC (PTCy + TOC) demonstrated prolonged survival compared to control mice. PTCy alone and PTCy + TOC-treated mice with hPBMCs showed minimal hepatic hCD33+ leukaemia cells, indicating sustained GVL immunity. Further, the combination of PTCy + TOC reduced histological damage in the lung and liver.
Conclusion
Collectively, this research demonstrates that PTCy alone or combined with TOC impairs GVHD without compromising GVL immunity.
{"title":"Graft-versus-leukaemia immunity is retained following treatment with post-transplant cyclophosphamide alone or combined with tocilizumab in humanised mice","authors":"Chloe Sligar, Ellie Reilly, Peter Cuthbertson, Kara L Vine, Katrina M Bird, Amal Elhage, Stephen I Alexander, Ronald Sluyter, Debbie Watson","doi":"10.1002/cti2.1497","DOIUrl":"https://doi.org/10.1002/cti2.1497","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Donor haematopoietic stem cell transplantation treats leukaemia by inducing graft-versus-leukaemia (GVL) immunity. However, this benefit is often mitigated by graft-versus-host disease (GVHD), which is reduced by post-transplant cyclophosphamide (PTCy) alone or combined with tocilizumab (TOC) in humanised mice. This study established a preclinical humanised mouse model of GVL and investigated whether PTCy alone or combined with TOC impacts GVL immunity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>NOD-<i>scid</i>-IL2Rγ<sup>null</sup> mice were injected with 2 × 10<sup>7</sup> human peripheral blood mononuclear cells (hPBMCs) on day 0 and with 1 × 10<sup>6</sup> THP-1 acute myeloid leukaemia cells on day 14. In subsequent experiments, mice were also injected with PTCy (33 mg kg<sup>−1</sup>) or Dulbecco's phosphate buffered saline (PBS) on days 3 and 4, alone or combined with TOC or control antibody (25 mg kg<sup>−1</sup>) twice weekly for 28 days. Clinical signs of disease were monitored until day 42.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Mice with hPBMCs from three different donors and THP-1 cells showed similar survival, clinical score and weight loss. hCD33<sup>+</sup> leukaemia cells were minimal in mice reconstituted with hPBMCs from two donors but present in mice with hPBMCs from a third donor, suggesting donor-specific GVL responses. hPBMC-injected mice treated with PTCy alone or combined with TOC (PTCy + TOC) demonstrated prolonged survival compared to control mice. PTCy alone and PTCy + TOC-treated mice with hPBMCs showed minimal hepatic hCD33<sup>+</sup> leukaemia cells, indicating sustained GVL immunity. Further, the combination of PTCy + TOC reduced histological damage in the lung and liver.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Collectively, this research demonstrates that PTCy alone or combined with TOC impairs GVHD without compromising GVL immunity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1497","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140135412","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}
Chun Zhang, Sun Chen, Yan Bian, Xiaohua Qian, Yurui Liu, Liqing Zhao, Jia Shen, Jiani Song, Peng Zhang, Lun Chen, Limin Jiang
Objectives
For children with Kawasaki disease (KD) at high risk of developing coronary artery lesions and requiring retreatment with intravenous immunoglobulin (IVIG), the availability of accurate prediction models remains limited because of inconsistent variables and unsatisfactory prediction results. We aimed to construct models to predict patient's probability of IVIG retreatment combining children's individual inflammatory characteristics.
Methods
Clinical manifestations and laboratory examinations of 266 children with KD were retrospectively analysed to build a development cohort data set (DC) and a validation cohort data set (VC). In the DC, binary logistic regression analyses were performed using R language. Nomograms and receiver operating curves were plotted. The concordance index (C index), net reclassification index, integrated discrimination improvement index and confusion matrix were applied to evaluate and validate the models.
Results
Models_5V and _9V were established. Both contained variables including the percentages of CD8+ T cells, CD4+ T cells, CD3+ T cells, levels of interleukin (IL)-2R and CRP. Model_9V additionally included variables for IL-6, TNF-α, NT-proBNP and sex, with a C index of 0.86 (95% CI 0.79–0.92). When model_9V was compared with model_5V, the NRI and IDI were 0.15 (95% CI 0.01–0.30, P < 0.01) and 0.07 (95% CI 0.02–0.12, P < 0.01). In the VC, the sensitivity, specificity and precision of model_9V were 1, 0.875 and 0.667, while those of model_5V were 0.833, 0.875 and 0.625.
Conclusion
Model_9V combined cytokine profiles and lymphocyte subsets with clinical characteristics and was superior to model_5V achieving satisfactory predictive power and providing a novel strategy early to identify patients who needed IVIG retreatment.
目的 对于有冠状动脉病变高风险并需要静脉注射免疫球蛋白（IVIG）再治疗的川崎病（KD）患儿，由于变量不一致和预测结果不理想，准确预测模型的可用性仍然有限。我们的目标是结合儿童的个体炎症特征，构建预测患者接受 IVIG 再治疗概率的模型。 方法 回顾性分析了266名KD患儿的临床表现和实验室检查，建立了开发队列数据集（DC）和验证队列数据集（VC）。在DC中，使用R语言进行了二元逻辑回归分析。绘制了提名图和接收者工作曲线。应用一致性指数（C 指数）、净再分类指数、综合辨别改进指数和混淆矩阵来评估和验证模型。 结果 建立了_5V 和_9V 模型。这两个模型都包含 CD8+ T 细胞、CD4+ T 细胞、CD3+ T 细胞百分比、白细胞介素（IL）-2R 水平和 CRP 等变量。模型 9V 还包括 IL-6、TNF-α、NT-proBNP 和性别等变量，C 指数为 0.86（95% CI 0.79-0.92）。模型 9V 与模型 5V 相比，NRI 和 IDI 分别为 0.15（95% CI 0.01-0.30，P< 0.01）和 0.07（95% CI 0.02-0.12，P< 0.01）。在 VC 中，模型_9V 的灵敏度、特异性和精确度分别为 1、0.875 和 0.667，而模型_5V 的灵敏度、特异性和精确度分别为 0.833、0.875 和 0.625。 结论 9V 模型将细胞因子图谱和淋巴细胞亚群与临床特征相结合，其预测能力优于 5V 模型，为早期识别需要 IVIG 再治疗的患者提供了一种新策略。
{"title":"Prediction of intravenous immunoglobulin retreatment in children with Kawasaki disease using models combining lymphocyte subset and cytokine profile in an East Asian cohort","authors":"Chun Zhang, Sun Chen, Yan Bian, Xiaohua Qian, Yurui Liu, Liqing Zhao, Jia Shen, Jiani Song, Peng Zhang, Lun Chen, Limin Jiang","doi":"10.1002/cti2.1498","DOIUrl":"https://doi.org/10.1002/cti2.1498","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>For children with Kawasaki disease (KD) at high risk of developing coronary artery lesions and requiring retreatment with intravenous immunoglobulin (IVIG), the availability of accurate prediction models remains limited because of inconsistent variables and unsatisfactory prediction results. We aimed to construct models to predict patient's probability of IVIG retreatment combining children's individual inflammatory characteristics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Clinical manifestations and laboratory examinations of 266 children with KD were retrospectively analysed to build a development cohort data set (DC) and a validation cohort data set (VC). In the DC, binary logistic regression analyses were performed using R language. Nomograms and receiver operating curves were plotted. The concordance index (C index), net reclassification index, integrated discrimination improvement index and confusion matrix were applied to evaluate and validate the models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Models_5V and _9V were established. Both contained variables including the percentages of CD8<sup>+</sup> T cells, CD4<sup>+</sup> T cells, CD3<sup>+</sup> T cells, levels of interleukin (IL)-2R and CRP. Model_9V additionally included variables for IL-6, TNF-α, NT-proBNP and sex, with a C index of 0.86 (95% CI 0.79–0.92). When model_9V was compared with model_5V, the NRI and IDI were 0.15 (95% CI 0.01–0.30, <i>P</i> < 0.01) and 0.07 (95% CI 0.02–0.12, <i>P</i> < 0.01). In the VC, the sensitivity, specificity and precision of model_9V were 1, 0.875 and 0.667, while those of model_5V were 0.833, 0.875 and 0.625.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Model_9V combined cytokine profiles and lymphocyte subsets with clinical characteristics and was superior to model_5V achieving satisfactory predictive power and providing a novel strategy early to identify patients who needed IVIG retreatment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1498","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140114287","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}
Donna Langley, Kate Zimmermann, Emma Krenske, Giorgio Stefanutti, Roy M Kimble, Andrew JA Holland, Mark W Fear, Fiona M Wood, Tony Kenna, Leila Cuttle
Objectives
The aim of this study was to characterise the dynamic immune profile of paediatric burn patients for up to 18 months post-burn.
Methods
Flow cytometry was used to measure 25 cell markers, chemokines and cytokines which reflected both pro-inflammatory and anti-inflammatory immune profiles. Peripheral blood mononuclear cells from 6 paediatric burn patients who had returned for repeated burn and scar treatments for > 4 timepoints within 12 months post-burn were compared to four age-matched healthy controls.
Results
While overall proportions of T cells, NK cells and macrophages remained relatively constant, over time percentages of these immune cells differentiated into effector and proinflammatory cell phenotypes including Th17 and activated γδ T cells. Circulating proportions of γδ T cells increased their expression of pro-inflammatory mediators throughout the burn recovery, with a 3–6 fold increase of IL-17 at 1–3 weeks, and NFκβ 9–18 months post-burn. T-regulatory cell plasticity was also observed, and Treg phenotype proportions changed from systemically reduced skin-homing T-regs (CCR4+) and increased inflammatory (CCR6+) at 1-month post-burn, to double-positive cell types (CCR4+CCR6+) elevated in circulation for 18 months post-burn. Furthermore, Tregs were observed to proportionally express less IL-10 but increased TNF-α over 18 months.
Conclusion
Overall, these results indicate the circulating percentages of immune cells do not increase or decrease over time post-burn, instead they become highly specialised, inflammatory and skin-homing. In this patient population, these changes persisted for at least 18 months post-burn, this ‘immune distraction’ may limit the ability of immune cells to prioritise other threats post-burn, such as respiratory infections.
{"title":"Unremitting pro-inflammatory T-cell phenotypes, and macrophage activity, following paediatric burn injury","authors":"Donna Langley, Kate Zimmermann, Emma Krenske, Giorgio Stefanutti, Roy M Kimble, Andrew JA Holland, Mark W Fear, Fiona M Wood, Tony Kenna, Leila Cuttle","doi":"10.1002/cti2.1496","DOIUrl":"https://doi.org/10.1002/cti2.1496","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The aim of this study was to characterise the dynamic immune profile of paediatric burn patients for up to 18 months post-burn.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Flow cytometry was used to measure 25 cell markers, chemokines and cytokines which reflected both pro-inflammatory and anti-inflammatory immune profiles. Peripheral blood mononuclear cells from 6 paediatric burn patients who had returned for repeated burn and scar treatments for > 4 timepoints within 12 months post-burn were compared to four age-matched healthy controls.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>While overall proportions of T cells, NK cells and macrophages remained relatively constant, over time percentages of these immune cells differentiated into effector and proinflammatory cell phenotypes including Th17 and activated γδ T cells. Circulating proportions of γδ T cells increased their expression of pro-inflammatory mediators throughout the burn recovery, with a 3–6 fold increase of IL-17 at 1–3 weeks, and NFκβ 9–18 months post-burn. T-regulatory cell plasticity was also observed, and Treg phenotype proportions changed from systemically reduced skin-homing T-regs (CCR4<sup>+</sup>) and increased inflammatory (CCR6<sup>+</sup>) at 1-month post-burn, to double-positive cell types (CCR4<sup>+</sup>CCR6<sup>+</sup>) elevated in circulation for 18 months post-burn. Furthermore, Tregs were observed to proportionally express less IL-10 but increased TNF-α over 18 months.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Overall, these results indicate the circulating percentages of immune cells do not increase or decrease over time post-burn, instead they become highly specialised, inflammatory and skin-homing. In this patient population, these changes persisted for at least 18 months post-burn, this ‘immune distraction’ may limit the ability of immune cells to prioritise other threats post-burn, such as respiratory infections.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1496","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140063852","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}
Ruth A Purcell, L Carissa Aurelia, Robyn Esterbauer, Lilith F Allen, Katherine A Bond, Deborah A Williamson, Janine M Trevillyan, Jason A Trubiano, Jennifer J Juno, Adam K Wheatley, Miles P Davenport, Thi HO Nguyen, Katherine Kedzierska, Stephen J Kent, Kevin John Selva, Amy W Chung
Objectives
Amino acid variations across more than 30 immunoglobulin (Ig) allotypes may introduce structural changes that influence recognition by anti-Ig detection reagents, consequently confounding interpretation of antibody responses, particularly in genetically diverse cohorts. Here, we assessed a panel of commercial monoclonal anti-IgG1 clones for capacity to universally recognise two dominant IgG1 haplotypes (G1m-1,3 and G1m1,17).
Methods
Four commercial monoclonal anti-human IgG1 clones were assessed via ELISAs and multiplex bead-based assays for their ability to bind G1m-1,3 and G1m1,17 IgG1 variants. Detection antibodies were validated against monoclonal IgG1 allotype standards and tested for capacity to recognise antigen-specific plasma IgG1 from G1m-1,3 and G1m1,17 homozygous and heterozygous SARS-CoV-2 BNT162b2 vaccinated (n = 28) and COVID-19 convalescent (n = 44) individuals. An Fc-specific pan-IgG detection antibody corroborated differences between hinge- and Fc-specific anti-IgG1 responses.
Results
Hinge-specific anti-IgG1 clone 4E3 preferentially bound G1m1,17 compared to G1m-1,3 IgG1. Consequently, SARS-CoV-2 Spike-specific IgG1 levels detected in G1m1,17/G1m1,17 BNT162b2 vaccinees appeared 9- to 17-fold higher than in G1m-1,3/G1m-1,3 vaccinees. Fc-specific IgG1 and pan-IgG detection antibodies equivalently bound G1m-1,3 and G1m1,17 IgG1 variants, and detected comparable Spike-specific IgG1 levels between haplotypes. IgG1 responses against other human coronaviruses and influenza were similarly poorly detected by 4E3 anti-IgG1 in G1m-1,3/G1m-1,3 subjects.
Conclusion
Anti-IgG1 clone 4E3 confounds assessment of antibody responses in clinical cohorts owing to bias towards detection of G1m1,17 IgG1 variants. Validation of anti-Ig clones should include evaluation of binding to relevant antibody variants, particularly as the role of immunogenetics upon humoral immunity is increasingly explored in diverse populations.
{"title":"Immunoglobulin G genetic variation can confound assessment of antibody levels via altered binding to detection reagents","authors":"Ruth A Purcell, L Carissa Aurelia, Robyn Esterbauer, Lilith F Allen, Katherine A Bond, Deborah A Williamson, Janine M Trevillyan, Jason A Trubiano, Jennifer J Juno, Adam K Wheatley, Miles P Davenport, Thi HO Nguyen, Katherine Kedzierska, Stephen J Kent, Kevin John Selva, Amy W Chung","doi":"10.1002/cti2.1494","DOIUrl":"https://doi.org/10.1002/cti2.1494","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Amino acid variations across more than 30 immunoglobulin (Ig) allotypes may introduce structural changes that influence recognition by anti-Ig detection reagents, consequently confounding interpretation of antibody responses, particularly in genetically diverse cohorts. Here, we assessed a panel of commercial monoclonal anti-IgG1 clones for capacity to universally recognise two dominant IgG1 haplotypes (G1m-1,3 and G1m1,17).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Four commercial monoclonal anti-human IgG1 clones were assessed via ELISAs and multiplex bead-based assays for their ability to bind G1m-1,3 and G1m1,17 IgG1 variants. Detection antibodies were validated against monoclonal IgG1 allotype standards and tested for capacity to recognise antigen-specific plasma IgG1 from G1m-1,3 and G1m1,17 homozygous and heterozygous SARS-CoV-2 BNT162b2 vaccinated (<i>n</i> = 28) and COVID-19 convalescent (<i>n</i> = 44) individuals. An Fc-specific <i>pan</i>-IgG detection antibody corroborated differences between hinge- and Fc-specific anti-IgG1 responses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Hinge-specific anti-IgG1 clone 4E3 preferentially bound G1m1,17 compared to G1m-1,3 IgG1. Consequently, SARS-CoV-2 Spike-specific IgG1 levels detected in G1m1,17/G1m1,17 BNT162b2 vaccinees appeared 9- to 17-fold higher than in G1m-1,3/G1m-1,3 vaccinees. Fc-specific IgG1 and <i>pan</i>-IgG detection antibodies equivalently bound G1m-1,3 and G1m1,17 IgG1 variants, and detected comparable Spike-specific IgG1 levels between haplotypes. IgG1 responses against other human coronaviruses and influenza were similarly poorly detected by 4E3 anti-IgG1 in G1m-1,3/G1m-1,3 subjects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Anti-IgG1 clone 4E3 confounds assessment of antibody responses in clinical cohorts owing to bias towards detection of G1m1,17 IgG1 variants. Validation of anti-Ig clones should include evaluation of binding to relevant antibody variants, particularly as the role of immunogenetics upon humoral immunity is increasingly explored in diverse populations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1494","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139993989","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}
Emerging evidence has demonstrated that tumour budding (TB) is negatively associated with T-lymphocyte infiltration in CRC. Despite extensive research, the molecular characteristics of immunologically ‘hot’ TB remain poorly understood.
Methods
We quantified the number of TB by haematoxylin–eosin (H&E) sections and the densities of CD3+ and CD8+ T-lymphocytes by immunohistochemistry in a CRC cohort of 351 cases who underwent curative resection. We analysed the differential expression and T-lymphocyte infiltration score of 37 human epithelial keratins in CRC using RNA sequencing from the TCGA dataset. In 278 TB-positive cases, KRT17 expression was evaluated in tumour centre (TC) and TB with a staining score. Patient demographic, clinicopathological features and survival rates were analysed.
Results
In a CRC cohort of 351 cases, low-grade TB was associated with high CD3+ and CD8+ T-cell densities in the invasive margin (IM) but not in the TC. Of 37 human epithelial keratins, only KRT17 expression in TB had an apparent association with TB-grade and T-lymphocyte infiltration. In 278 TB-positive cases, high KRT17 expression in TB (KRT17TB) was negatively associated with low-grade TB and positively associated with high CD3+ and CD8+ T-cell densities in IM. High KRT17TB predicted early tumour grade, absence of lymph node metastasis and absence of tumour deposits. Additionally, patients with high KRT17TB had good overall survival and disease-free survival. Notably, low KRT17TB can specifically identify those patients with a poor prognosis among colorectal cancer patients with low TB and high T-lymphocyte infiltration.
Conclusions
KRT17 can be employed as a new indicator for distinguishing different immunological TBs.
目的 新的证据表明，肿瘤萌芽（TB）与 T 淋巴细胞在 CRC 中的浸润呈负相关。尽管开展了大量研究，但人们对免疫学 "热点 "TB 的分子特征仍然知之甚少。 方法 我们通过血栓素-伊红（H&E）切片和免疫组化方法对 351 例接受根治性切除的 CRC 病例中 CD3+ 和 CD8+ T 淋巴细胞的密度进行了量化。我们利用 TCGA 数据集的 RNA 测序分析了 37 种人类上皮角蛋白在 CRC 中的差异表达和 T 淋巴细胞浸润评分。在278例TB阳性病例中，通过染色评分评估了KRT17在肿瘤中心（TC）和TB中的表达。分析了患者的人口统计学特征、临床病理学特征和生存率。 结果 在 351 例 CRC 队列中，低级别 TB 与浸润边缘（IM）的高 CD3+ 和 CD8+ T 细胞密度有关，但与 TC 无关。在 37 种人类上皮角蛋白中，只有 KRT17 在结核中的表达与结核分级和 T 淋巴细胞浸润有明显关联。在 278 例结核阳性病例中，结核中 KRT17 的高表达（KRT17TB）与低级别结核呈负相关，与 IM 中 CD3+ 和 CD8+ T 细胞的高密度呈正相关。高 KRT17TB 预测早期肿瘤分级、无淋巴结转移和无肿瘤沉积。此外，KRT17TB 高的患者总生存期和无病生存期都很好。值得注意的是，低 KRT17TB 可以在低 TB 和高 T 淋巴细胞浸润的结直肠癌患者中识别出预后较差的患者。 结论 KRT17 可作为区分不同免疫性结核的新指标。
{"title":"High KRT17 expression in tumour budding indicates immunologically ‘hot’ tumour budding and predicts good survival in patients with colorectal cancer","authors":"Wenfeng Liang, Haiqing Jie, Hao Xie, Yebohao Zhou, Wenxin Li, Liang Huang, Zhenxing Liang, Huashan Liu, Xiaobin Zheng, Ziwei Zeng, Liang Kang","doi":"10.1002/cti2.1495","DOIUrl":"https://doi.org/10.1002/cti2.1495","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Emerging evidence has demonstrated that tumour budding (TB) is negatively associated with T-lymphocyte infiltration in CRC. Despite extensive research, the molecular characteristics of immunologically ‘hot’ TB remain poorly understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We quantified the number of TB by haematoxylin–eosin (H&E) sections and the densities of CD3<sup>+</sup> and CD8<sup>+</sup> T-lymphocytes by immunohistochemistry in a CRC cohort of 351 cases who underwent curative resection. We analysed the differential expression and T-lymphocyte infiltration score of 37 human epithelial keratins in CRC using RNA sequencing from the TCGA dataset. In 278 TB-positive cases, KRT17 expression was evaluated in tumour centre (TC) and TB with a staining score. Patient demographic, clinicopathological features and survival rates were analysed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In a CRC cohort of 351 cases, low-grade TB was associated with high CD3<sup>+</sup> and CD8<sup>+</sup> T-cell densities in the invasive margin (IM) but not in the TC. Of 37 human epithelial keratins, only KRT17 expression in TB had an apparent association with TB-grade and T-lymphocyte infiltration. In 278 TB-positive cases, high KRT17 expression in TB (KRT17TB) was negatively associated with low-grade TB and positively associated with high CD3<sup>+</sup> and CD8<sup>+</sup> T-cell densities in IM. High KRT17TB predicted early tumour grade, absence of lymph node metastasis and absence of tumour deposits. Additionally, patients with high KRT17TB had good overall survival and disease-free survival. Notably, low KRT17TB can specifically identify those patients with a poor prognosis among colorectal cancer patients with low TB and high T-lymphocyte infiltration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>KRT17 can be employed as a new indicator for distinguishing different immunological TBs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1495","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139993990","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}
Dominant-activating (DA) lesions in RAC2 have been reported in 18 individuals to date. Some have required haematopoietic stem cell transplantation (HSCT) for their (severe) combined immunodeficiency syndrome phenotype. We aimed to investigate clinical and cellular features of a kindred harbouring a novel variant in RAC2 p.Ile21Ser (I21S) to better understand DA lesions' phenotypic spectrum.
Methods
Clinical and immunological information was collated for seven living individuals from the same kindred with RAC2 p.I21S. We evaluated neutrophil morphology, RAC2 protein expression and superoxide production using freshly isolated neutrophils stimulated with phorbol-12-myristate-13-acetate (PMA) and N-formyl-MetLeuPhe (fMLP).
Results
Patient 1 (P1, aged 11, male) has a history of bacterial suppurative otitis media, viral and bacterial cutaneous infections. P1's siblings (P2, P3), mother (P4), maternal aunt (P5) and uncle (P6) have similar infection histories. P1's maternal cousin (P7) presented with Burkitt's lymphoma at age 9. All affected individuals are alive and none has required HSCT to date. They have chronic lymphopenia affecting the CD4+T and B-cell compartments. P1–3 have isolated reduction in IgM levels whereas the adults universally have normal immunoglobulins. Specific antibody responses are preserved. Affected individuals have neutrophil vacuolation, and their neutrophils have enhanced superoxide production compared to healthy controls.
Conclusion
RAC2 p.I21S is an activating variant causing notable morphological and functional abnormalities similar to other reported DA mutations. This novel variant expands the broad clinical phenotypic spectrum of RAC2 DA lesions, emphasising the need to tailor clinical management according to patients' disease phenotype and severity.
迄今为止，已有18人报告了RAC2的显性激活（DA）病变。其中一些人需要进行造血干细胞移植（HSCT）来治疗其（重度）联合免疫缺陷综合征表型。我们的目的是调查一个携带 RAC2 p.Ile21Ser (I21S) 新型变异体的同类的临床和细胞特征，以更好地了解 DA 病变的表型谱。
{"title":"Phenotypic spectrum in a family with a novel RAC2 p.I21S dominant-activating mutation","authors":"Louisa Ashby, Lydia Chan, Christine Winterbourn, See-Tarn Woon, Paula Keating, Raoul Heller, Rohan Ameratunga, Ignatius Chua, Kuang-Chih Hsiao","doi":"10.1002/cti2.1493","DOIUrl":"10.1002/cti2.1493","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Dominant-activating (DA) lesions in <i>RAC2</i> have been reported in 18 individuals to date. Some have required haematopoietic stem cell transplantation (HSCT) for their (severe) combined immunodeficiency syndrome phenotype. We aimed to investigate clinical and cellular features of a kindred harbouring a novel variant in <i>RAC2</i> p.Ile21Ser (I21S) to better understand DA lesions' phenotypic spectrum.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Clinical and immunological information was collated for seven living individuals from the same kindred with <i>RAC2</i> p.I21S. We evaluated neutrophil morphology, RAC2 protein expression and superoxide production using freshly isolated neutrophils stimulated with phorbol-12-myristate-13-acetate (PMA) and N-formyl-MetLeuPhe (fMLP).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Patient 1 (P1, aged 11, male) has a history of bacterial suppurative otitis media, viral and bacterial cutaneous infections. P1's siblings (P2, P3), mother (P4), maternal aunt (P5) and uncle (P6) have similar infection histories. P1's maternal cousin (P7) presented with Burkitt's lymphoma at age 9. All affected individuals are alive and none has required HSCT to date. They have chronic lymphopenia affecting the CD4<sup>+</sup>T and B-cell compartments. P1–3 have isolated reduction in IgM levels whereas the adults universally have normal immunoglobulins. Specific antibody responses are preserved. Affected individuals have neutrophil vacuolation, and their neutrophils have enhanced superoxide production compared to healthy controls.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p><i>RAC2</i> p.I21S is an activating variant causing notable morphological and functional abnormalities similar to other reported DA mutations. This novel variant expands the broad clinical phenotypic spectrum of <i>RAC2</i> DA lesions, emphasising the need to tailor clinical management according to patients' disease phenotype and severity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1493","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139969324","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}
Katherine R Martin, Cristina Gamell, Tsin Yee Tai, Roberto Bonelli, Jacinta Hansen, James Tatoulis, Monther Alhamdoosh, Nicholas Wilson, Ian Wicks
Objectives
Systemic inflammatory response syndrome (SIRS) is a frequent complication of cardiopulmonary bypass (CPB). SIRS is associated with significant morbidity and mortality, but its pathogenesis remains incompletely understood, and as a result, biomarkers are lacking and treatment remains expectant and supportive. This study aimed to understand the pathophysiological mechanisms driving SIRS induced by CPB and identify novel therapeutic targets that might reduce systemic inflammation and improve patient outcomes.
Methods
Twenty-one patients undergoing cardiac surgery and CPB were recruited, and blood was sampled before, during and after surgery. SIRS was defined using the American College of Chest Physicians/Society of Critical Care Medicine criteria. We performed immune cell profiling and whole blood transcriptomics and measured individual mediators in plasma/serum to characterise SIRS induced by CPB.
Results
Nineteen patients fulfilled criteria for SIRS, with a mean duration of 2.7 days. Neutrophil numbers rose rapidly with CPB and remained elevated for at least 48 h afterwards. Transcriptional signatures associated with neutrophil activation and degranulation were enriched during CPB. We identified a network of cytokines governing these transcriptional changes, including granulocyte colony-stimulating factor (G-CSF), a regulator of neutrophil production and function.
Conclusions
We identified neutrophils and G-CSF as major regulators of CPB-induced systemic inflammation. Short-term targeting of G-CSF could provide a novel therapeutic strategy to limit neutrophil-mediated inflammation and tissue damage in SIRS induced by CPB.
{"title":"Whole blood transcriptomics reveals granulocyte colony-stimulating factor as a mediator of cardiopulmonary bypass-induced systemic inflammatory response syndrome","authors":"Katherine R Martin, Cristina Gamell, Tsin Yee Tai, Roberto Bonelli, Jacinta Hansen, James Tatoulis, Monther Alhamdoosh, Nicholas Wilson, Ian Wicks","doi":"10.1002/cti2.1490","DOIUrl":"https://doi.org/10.1002/cti2.1490","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Systemic inflammatory response syndrome (SIRS) is a frequent complication of cardiopulmonary bypass (CPB). SIRS is associated with significant morbidity and mortality, but its pathogenesis remains incompletely understood, and as a result, biomarkers are lacking and treatment remains expectant and supportive. This study aimed to understand the pathophysiological mechanisms driving SIRS induced by CPB and identify novel therapeutic targets that might reduce systemic inflammation and improve patient outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Twenty-one patients undergoing cardiac surgery and CPB were recruited, and blood was sampled before, during and after surgery. SIRS was defined using the American College of Chest Physicians/Society of Critical Care Medicine criteria. We performed immune cell profiling and whole blood transcriptomics and measured individual mediators in plasma/serum to characterise SIRS induced by CPB.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Nineteen patients fulfilled criteria for SIRS, with a mean duration of 2.7 days. Neutrophil numbers rose rapidly with CPB and remained elevated for at least 48 h afterwards. Transcriptional signatures associated with neutrophil activation and degranulation were enriched during CPB. We identified a network of cytokines governing these transcriptional changes, including granulocyte colony-stimulating factor (G-CSF), a regulator of neutrophil production and function.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We identified neutrophils and G-CSF as major regulators of CPB-induced systemic inflammation. Short-term targeting of G-CSF could provide a novel therapeutic strategy to limit neutrophil-mediated inflammation and tissue damage in SIRS induced by CPB.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1490","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139901690","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}
Isabella A Revesz, Paul Joyce, Lisa M Ebert, Clive A Prestidge
γδ T cells are a unique subset of T lymphocytes, exhibiting features of both innate and adaptive immune cells and are involved with cancer immunosurveillance. They present an attractive alternative to conventional T cell-based immunotherapy due, in large part, to their lack of major histocompatibility (MHC) restriction and ability to secrete high levels of cytokines with well-known anti-tumour functions. To date, clinical trials using γδ T cell-based immunotherapy for a range of haematological and solid cancers have yielded limited success compared with in vitro studies. This inability to translate the efficacy of γδ T-cell therapies from preclinical to clinical trials is attributed to a combination of several factors, e.g. γδ T-cell agonists that are commonly used to stimulate populations of these cells have limited cellular uptake yet rely on intracellular mechanisms; administered γδ T cells display low levels of tumour-infiltration; and there is a gap in the understanding of γδ T-cell inhibitory receptors. This review explores the discrepancy between γδ T-cell clinical and preclinical performance and offers viable avenues to overcome these obstacles. Using more direct γδ T-cell agonists, encapsulating these agonists into lipid nanocarriers to improve their pharmacokinetic and pharmacodynamic profiles and the use of combination therapies to overcome checkpoint inhibition and T-cell exhaustion are ways to bridge the gap between preclinical and clinical success. Given the ability to overcome these limitations, the development of a more targeted γδ T-cell agonist-checkpoint blockade combination therapy has the potential for success in clinical trials which has to date remained elusive.
γδ T 细胞是 T 淋巴细胞的一个独特亚群，同时具有先天性免疫细胞和适应性免疫细胞的特征，参与癌症免疫监视。γδT细胞是传统T细胞免疫疗法的一个极具吸引力的替代选择，这在很大程度上是因为γδT细胞不受主要组织相容性（MHC）的限制，而且能分泌高水平的细胞因子，具有众所周知的抗肿瘤功能。迄今为止，与体外研究相比，使用γδ T 细胞免疫疗法治疗一系列血液病和实体瘤的临床试验取得的成功有限。γδT细胞疗法无法从临床前试验转化为临床试验的原因是多种因素的综合作用，例如，常用于刺激这些细胞群的γδT细胞激动剂对细胞的吸收有限，但却依赖于细胞内机制；给药的γδT细胞显示出较低的肿瘤浸润水平；以及对γδT细胞抑制受体的认识存在差距。本综述探讨了 γδ T 细胞临床表现与临床前表现之间的差异，并提出了克服这些障碍的可行途径。使用更直接的 γδ T 细胞激动剂、将这些激动剂封装到脂质纳米载体中以改善其药代动力学和药效学特征，以及使用联合疗法来克服检查点抑制和 T 细胞衰竭，都是弥合临床前和临床成功之间差距的方法。考虑到克服这些限制的能力，开发更有针对性的γδ T细胞激动剂-检查点阻断联合疗法有可能在临床试验中取得成功，而迄今为止，这种疗法仍未取得成功。
{"title":"Effective γδ T-cell clinical therapies: current limitations and future perspectives for cancer immunotherapy","authors":"Isabella A Revesz, Paul Joyce, Lisa M Ebert, Clive A Prestidge","doi":"10.1002/cti2.1492","DOIUrl":"https://doi.org/10.1002/cti2.1492","url":null,"abstract":"<p>γδ T cells are a unique subset of T lymphocytes, exhibiting features of both innate and adaptive immune cells and are involved with cancer immunosurveillance. They present an attractive alternative to conventional T cell-based immunotherapy due, in large part, to their lack of major histocompatibility (MHC) restriction and ability to secrete high levels of cytokines with well-known anti-tumour functions. To date, clinical trials using γδ T cell-based immunotherapy for a range of haematological and solid cancers have yielded limited success compared with <i>in vitro</i> studies. This inability to translate the efficacy of γδ T-cell therapies from preclinical to clinical trials is attributed to a combination of several factors, e.g. γδ T-cell agonists that are commonly used to stimulate populations of these cells have limited cellular uptake yet rely on intracellular mechanisms; administered γδ T cells display low levels of tumour-infiltration; and there is a gap in the understanding of γδ T-cell inhibitory receptors. This review explores the discrepancy between γδ T-cell clinical and preclinical performance and offers viable avenues to overcome these obstacles. Using more direct γδ T-cell agonists, encapsulating these agonists into lipid nanocarriers to improve their pharmacokinetic and pharmacodynamic profiles and the use of combination therapies to overcome checkpoint inhibition and T-cell exhaustion are ways to bridge the gap between preclinical and clinical success. Given the ability to overcome these limitations, the development of a more targeted γδ T-cell agonist-checkpoint blockade combination therapy has the potential for success in clinical trials which has to date remained elusive.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1492","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139901691","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}
Seasonal influenza viruses continue to cause severe medical and financial complications annually. Although there are many licenced influenza vaccines, there are billions of cases of influenza infection every year, resulting in the death of over half a million individuals. Furthermore, these figures can rise in the event of a pandemic, as seen throughout history, like the 1918 Spanish influenza pandemic (50 million deaths) and the 1968 Hong Kong influenza pandemic (~4 million deaths). In this review, we have summarised many of the currently licenced influenza vaccines available across the world and current vaccines in clinical trials. We then briefly discuss the important role of CD8+ T cells during influenza infection and why future influenza vaccines should consider targeting CD8+ T cells. Finally, we assess the current landscape of known immunogenic CD8+ T-cell epitopes and highlight the knowledge gaps required to be filled for the design of rational future influenza vaccines that incorporate CD8+ T cells.
季节性流感病毒每年都会引发严重的医疗和经济并发症。尽管有许多获得许可的流感疫苗，但每年仍有数十亿例流感感染病例，导致 50 多万人死亡。此外，在流感大流行的情况下，这些数字还会上升，这在历史上也曾发生过，如 1918 年西班牙流感大流行（5000 万人死亡）和 1968 年香港流感大流行（约 400 万人死亡）。在这篇综述中，我们总结了目前全球许多获得许可的流感疫苗以及正在进行临床试验的疫苗。然后，我们简要讨论了 CD8+ T 细胞在流感感染过程中的重要作用，以及为什么未来的流感疫苗应考虑以 CD8+ T 细胞为靶标。最后，我们对目前已知的免疫原性 CD8+ T 细胞表位进行了评估，并强调了在设计包含 CD8+ T 细胞的合理未来流感疫苗时需要填补的知识空白。
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