Pub Date : 2024-09-11DOI: 10.1038/s43018-024-00821-1
Laura Carretero-Iglesia, Olivia J. Hall, Jérémy Berret, Daniela Pais, Carole Estoppey, Myriam Chimen, Thierry Monney, Jeremy Loyau, Cyrille Dreyfus, Julie Macoin, Cynthia Perez, Vinu Menon, Isabelle Gruber, Amélie Laurendon, Lydia N. Caro, Girish S. Gudi, Tomomi Matsuura, Piet H. van der Graaf, Stanislas Blein, M. Lamine Mbow, Rebecca Croasdale-Wood, Ankita Srivastava, Michael R. Dyson, Thomas Matthes, Zeynep Kaya, Claire M. Edwards, James R. Edwards, Sophie Maiga, Catherine Pellat-Deceunynck, Cyrille Touzeau, Philippe Moreau, Cyril Konto, Adam Drake, Eugene A. Zhukovsky, Mario Perro, Maria Pihlgren
Despite recent advances in immunotherapies targeting single tumor-associated antigens, patients with multiple myeloma eventually relapse. ISB 2001 is a CD3+ T cell engager (TCE) co-targeting BCMA and CD38 designed to improve cytotoxicity against multiple myeloma. Targeting of two tumor-associated antigens by a single TCE resulted in superior cytotoxic potency across a variable range of BCMA and CD38 tumor expression profiles mimicking natural tumor heterogeneity, improved resistance to competing soluble factors and exhibited superior cytotoxic potency on patient-derived samples and in mouse models. Despite the broad expression of CD38 across human tissues, ISB 2001 demonstrated a reduced T cell activation profile in the absence of tumor cells when compared to TCEs targeting CD38 only. To determine an optimal first-in-human dose for the ongoing clinical trial ( NCT05862012 ), we developed an innovative quantitative systems pharmacology model leveraging preclinical data, using a minimum pharmacologically active dose approach, therefore reducing patient exposure to subefficacious doses of therapies. Perro and colleagues develop a CD3+ T cell engager co-targeting BCMA and CD38 to improve immunotherapy for multiple myeloma, demonstrate cytotoxicity in patient-derived samples and murine models and develop a quantitative systems pharmacology model.
{"title":"ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells","authors":"Laura Carretero-Iglesia, Olivia J. Hall, Jérémy Berret, Daniela Pais, Carole Estoppey, Myriam Chimen, Thierry Monney, Jeremy Loyau, Cyrille Dreyfus, Julie Macoin, Cynthia Perez, Vinu Menon, Isabelle Gruber, Amélie Laurendon, Lydia N. Caro, Girish S. Gudi, Tomomi Matsuura, Piet H. van der Graaf, Stanislas Blein, M. Lamine Mbow, Rebecca Croasdale-Wood, Ankita Srivastava, Michael R. Dyson, Thomas Matthes, Zeynep Kaya, Claire M. Edwards, James R. Edwards, Sophie Maiga, Catherine Pellat-Deceunynck, Cyrille Touzeau, Philippe Moreau, Cyril Konto, Adam Drake, Eugene A. Zhukovsky, Mario Perro, Maria Pihlgren","doi":"10.1038/s43018-024-00821-1","DOIUrl":"10.1038/s43018-024-00821-1","url":null,"abstract":"Despite recent advances in immunotherapies targeting single tumor-associated antigens, patients with multiple myeloma eventually relapse. ISB 2001 is a CD3+ T cell engager (TCE) co-targeting BCMA and CD38 designed to improve cytotoxicity against multiple myeloma. Targeting of two tumor-associated antigens by a single TCE resulted in superior cytotoxic potency across a variable range of BCMA and CD38 tumor expression profiles mimicking natural tumor heterogeneity, improved resistance to competing soluble factors and exhibited superior cytotoxic potency on patient-derived samples and in mouse models. Despite the broad expression of CD38 across human tissues, ISB 2001 demonstrated a reduced T cell activation profile in the absence of tumor cells when compared to TCEs targeting CD38 only. To determine an optimal first-in-human dose for the ongoing clinical trial ( NCT05862012 ), we developed an innovative quantitative systems pharmacology model leveraging preclinical data, using a minimum pharmacologically active dose approach, therefore reducing patient exposure to subefficacious doses of therapies. Perro and colleagues develop a CD3+ T cell engager co-targeting BCMA and CD38 to improve immunotherapy for multiple myeloma, demonstrate cytotoxicity in patient-derived samples and murine models and develop a quantitative systems pharmacology model.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 10","pages":"1494-1514"},"PeriodicalIF":23.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43018-024-00821-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142175804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-11DOI: 10.1038/s43018-024-00815-z
The anti-apoptotic protein MCL1 is a therapeutic target in cancer, but long-term MCL1 inhibition has been found to increase the risk of cardiotoxicity. We developed BRD-810 as a potent and selective MCL1 inhibitor that induces cancer cell death in vivo within a few hours. As BRD-810 was designed to be rapidly cleared, it targets cancer cells while minimizing the risk for cardiotoxicity.
{"title":"MCL1 inhibitor BRD-810 kills cancer cells while minimizing risk of cardiotoxicity","authors":"","doi":"10.1038/s43018-024-00815-z","DOIUrl":"10.1038/s43018-024-00815-z","url":null,"abstract":"The anti-apoptotic protein MCL1 is a therapeutic target in cancer, but long-term MCL1 inhibition has been found to increase the risk of cardiotoxicity. We developed BRD-810 as a potent and selective MCL1 inhibitor that induces cancer cell death in vivo within a few hours. As BRD-810 was designed to be rapidly cleared, it targets cancer cells while minimizing the risk for cardiotoxicity.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 10","pages":"1457-1458"},"PeriodicalIF":23.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142175802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-11DOI: 10.1038/s43018-024-00805-1
Sigrid R. Ruuls, Paul W. H. I. Parren
In the ongoing search for innovative treatments to combat refractory and relapsed cancer, new preclinical work in multiple myeloma shows that increasing binding avidity by targeting two antigens in one T cell-engaging trispecific antibody boosts anti-tumor activity and reduces the likelihood of tumor escape relative to current antibody-based therapies.
{"title":"Antibody avidity meets multiple myeloma","authors":"Sigrid R. Ruuls, Paul W. H. I. Parren","doi":"10.1038/s43018-024-00805-1","DOIUrl":"10.1038/s43018-024-00805-1","url":null,"abstract":"In the ongoing search for innovative treatments to combat refractory and relapsed cancer, new preclinical work in multiple myeloma shows that increasing binding avidity by targeting two antigens in one T cell-engaging trispecific antibody boosts anti-tumor activity and reduces the likelihood of tumor escape relative to current antibody-based therapies.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 10","pages":"1452-1454"},"PeriodicalIF":23.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142175801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1038/s43018-024-00822-0
Kaiwen Li, Wenlong Zhong, Jinhai Fan, Shaogang Wang, Dexin Yu, Tao Xu, Jiaju Lyu, Shaoxu Wu, Tao Qin, Zhuo Wu, Longhao Xu, Kaijie Wu, Zheng Liu, Zhiquan Hu, Fan Li, Jinyou Wang, Qi Wang, Jie Min, Zhiqiang Zhang, Luping Yu, Sentai Ding, Longfei Huang, Tingting Zhao, Jian Huang, Tianxin Lin
Programmed death 1 blockade (tislelizumab) has been approved for metastatic urothelial carcinoma but not as part of neoadjuvant therapy for muscle-invasive bladder cancer (MIBC). In this multicenter single-arm trial (ChiCTR2000037670), 65 participants with cT2-4aN0M0 MIBC received neoadjuvant gemcitabine–cisplatin plus tislelizumab; 57 of them underwent radical cystectomy (RC). The primary endpoint of pathologic complete response (pCR) rate was 50.9% (29/57, 95% confidence interval (CI) 37.3–64.4%) and the pathologic downstaging (secondary endpoint) rate was 75.4% (43/57, 95% CI 62.2–85.9%) in participants undergoing RC. Genomic and transcriptomic analyses revealed three MIBC molecular subtypes (S): S1 (immune-desert) with activated cell-cycle pathway, S2 (immune-excluded) with activated transforming growth factor-β pathway and S3 (immune-inflamed) with upregulated interferon-α and interferon-γ response. Post hoc analysis showed pCR rates of 16% (3/19, S1), 77% (10/13, S2) and 80% (12/15, S3) (P = 0.006). In conclusion, neoadjuvant gemcitabine–cisplatin plus tislelizumab for MIBC was compatible with an enhanced pCR rate. Li et al. perform a phase 2 single-arm clinical trial of neoadjuvant chemotherapy plus checkpoint blockade in participants with resectable muscle-invasive bladder cancer and conduct genomic and transcriptomic profiling to describe molecular subtypes.
{"title":"Neoadjuvant gemcitabine–cisplatin plus tislelizumab in persons with resectable muscle-invasive bladder cancer: a multicenter, single-arm, phase 2 trial","authors":"Kaiwen Li, Wenlong Zhong, Jinhai Fan, Shaogang Wang, Dexin Yu, Tao Xu, Jiaju Lyu, Shaoxu Wu, Tao Qin, Zhuo Wu, Longhao Xu, Kaijie Wu, Zheng Liu, Zhiquan Hu, Fan Li, Jinyou Wang, Qi Wang, Jie Min, Zhiqiang Zhang, Luping Yu, Sentai Ding, Longfei Huang, Tingting Zhao, Jian Huang, Tianxin Lin","doi":"10.1038/s43018-024-00822-0","DOIUrl":"10.1038/s43018-024-00822-0","url":null,"abstract":"Programmed death 1 blockade (tislelizumab) has been approved for metastatic urothelial carcinoma but not as part of neoadjuvant therapy for muscle-invasive bladder cancer (MIBC). In this multicenter single-arm trial (ChiCTR2000037670), 65 participants with cT2-4aN0M0 MIBC received neoadjuvant gemcitabine–cisplatin plus tislelizumab; 57 of them underwent radical cystectomy (RC). The primary endpoint of pathologic complete response (pCR) rate was 50.9% (29/57, 95% confidence interval (CI) 37.3–64.4%) and the pathologic downstaging (secondary endpoint) rate was 75.4% (43/57, 95% CI 62.2–85.9%) in participants undergoing RC. Genomic and transcriptomic analyses revealed three MIBC molecular subtypes (S): S1 (immune-desert) with activated cell-cycle pathway, S2 (immune-excluded) with activated transforming growth factor-β pathway and S3 (immune-inflamed) with upregulated interferon-α and interferon-γ response. Post hoc analysis showed pCR rates of 16% (3/19, S1), 77% (10/13, S2) and 80% (12/15, S3) (P = 0.006). In conclusion, neoadjuvant gemcitabine–cisplatin plus tislelizumab for MIBC was compatible with an enhanced pCR rate. Li et al. perform a phase 2 single-arm clinical trial of neoadjuvant chemotherapy plus checkpoint blockade in participants with resectable muscle-invasive bladder cancer and conduct genomic and transcriptomic profiling to describe molecular subtypes.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 10","pages":"1465-1478"},"PeriodicalIF":23.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142175803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Prostate cancer (PCa) exhibits significant geoethnic disparities as reflected by distinct variations in the cancer genome and disease progression. Here, we perform a comprehensive proteogenomic characterization of localized high-risk PCa utilizing paired tumors and nearby tissues from 125 Chinese male patients, with the primary objectives of identifying potential biomarkers, unraveling critical oncogenic events and delineating molecular subtypes with poor prognosis. Our integrated analysis highlights the utility of GOLM1 as a noninvasive serum biomarker. Phosphoproteomics analysis reveals the crucial role of Ser331 phosphorylation on FOXA1 in regulating FOXA1-AR-dependent cistrome. Notably, our proteomic profiling identifies three distinct subtypes, with metabolic immune-desert tumors (S-III) emerging as a particularly aggressive subtype linked to poor prognosis and BCAT2 catabolism-driven PCa progression. In summary, our study provides a comprehensive resource detailing the unique proteomic and phosphoproteomic characteristics of PCa molecular pathogenesis and offering valuable insights for the development of diagnostic and therapeutic strategies. Dong et al. present an integrative proteogenomic analysis of high-risk prostate cancer samples from a cohort of Chinese patients and highlight potential therapeutic vulnerabilities and diagnostic markers.
{"title":"Integrative proteogenomic profiling of high-risk prostate cancer samples from Chinese patients indicates metabolic vulnerabilities and diagnostic biomarkers","authors":"Baijun Dong, Jun-Yu Xu, Yuqi Huang, Jiacheng Guo, Qun Dong, Yanqing Wang, Ni Li, Qiuli Liu, Mingya Zhang, Qiang Pan, Hanling Wang, Jun Jiang, Bairun Chen, Danqing Shen, Yiming Ma, Linhui Zhai, Jian Zhang, Jing Li, Wei Xue, Minjia Tan, Jun Qin","doi":"10.1038/s43018-024-00820-2","DOIUrl":"10.1038/s43018-024-00820-2","url":null,"abstract":"Prostate cancer (PCa) exhibits significant geoethnic disparities as reflected by distinct variations in the cancer genome and disease progression. Here, we perform a comprehensive proteogenomic characterization of localized high-risk PCa utilizing paired tumors and nearby tissues from 125 Chinese male patients, with the primary objectives of identifying potential biomarkers, unraveling critical oncogenic events and delineating molecular subtypes with poor prognosis. Our integrated analysis highlights the utility of GOLM1 as a noninvasive serum biomarker. Phosphoproteomics analysis reveals the crucial role of Ser331 phosphorylation on FOXA1 in regulating FOXA1-AR-dependent cistrome. Notably, our proteomic profiling identifies three distinct subtypes, with metabolic immune-desert tumors (S-III) emerging as a particularly aggressive subtype linked to poor prognosis and BCAT2 catabolism-driven PCa progression. In summary, our study provides a comprehensive resource detailing the unique proteomic and phosphoproteomic characteristics of PCa molecular pathogenesis and offering valuable insights for the development of diagnostic and therapeutic strategies. Dong et al. present an integrative proteogenomic analysis of high-risk prostate cancer samples from a cohort of Chinese patients and highlight potential therapeutic vulnerabilities and diagnostic markers.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 9","pages":"1427-1447"},"PeriodicalIF":23.5,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1038/s43018-024-00817-x
Jun Li, Wei Liu, Kamalika Mojumdar, Hong Kim, Zhicheng Zhou, Zhenlin Ju, Shwetha V. Kumar, Patrick Kwok-Shing Ng, Han Chen, Michael A. Davies, Yiling Lu, Rehan Akbani, Gordon B. Mills, Han Liang
The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) are foundational resources in cancer research, providing extensive molecular and phenotypic data. However, large-scale proteomic data across various cancer types for these cohorts remain limited. Here, we expand upon our previous work to generate high-quality protein expression data for approximately 8,000 TCGA patient samples and around 900 CCLE cell line samples, covering 447 clinically relevant proteins, using reverse-phase protein arrays. These protein expression profiles offer profound insights into intertumor heterogeneity and cancer dependency and serve as sensitive functional readouts for somatic alterations. We develop a systematic protein-centered strategy for identifying synthetic lethality pairs and experimentally validate an interaction between protein kinase A subunit α and epidermal growth factor receptor. We also identify metastasis-related protein markers with clinical relevance. This dataset represents a valuable resource for advancing our understanding of cancer mechanisms, discovering protein biomarkers and developing innovative therapeutic strategies. Liang and colleagues establish a high-quality protein expression resource for 8,000 The Cancer Genome Atlas patient samples and 900 Cancer Cell Line Encyclopedia cell lines for approximately 450 proteins, which they use to identify synthetic lethality pairs and metastasis markers.
{"title":"A protein expression atlas on tissue samples and cell lines from cancer patients provides insights into tumor heterogeneity and dependencies","authors":"Jun Li, Wei Liu, Kamalika Mojumdar, Hong Kim, Zhicheng Zhou, Zhenlin Ju, Shwetha V. Kumar, Patrick Kwok-Shing Ng, Han Chen, Michael A. Davies, Yiling Lu, Rehan Akbani, Gordon B. Mills, Han Liang","doi":"10.1038/s43018-024-00817-x","DOIUrl":"10.1038/s43018-024-00817-x","url":null,"abstract":"The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) are foundational resources in cancer research, providing extensive molecular and phenotypic data. However, large-scale proteomic data across various cancer types for these cohorts remain limited. Here, we expand upon our previous work to generate high-quality protein expression data for approximately 8,000 TCGA patient samples and around 900 CCLE cell line samples, covering 447 clinically relevant proteins, using reverse-phase protein arrays. These protein expression profiles offer profound insights into intertumor heterogeneity and cancer dependency and serve as sensitive functional readouts for somatic alterations. We develop a systematic protein-centered strategy for identifying synthetic lethality pairs and experimentally validate an interaction between protein kinase A subunit α and epidermal growth factor receptor. We also identify metastasis-related protein markers with clinical relevance. This dataset represents a valuable resource for advancing our understanding of cancer mechanisms, discovering protein biomarkers and developing innovative therapeutic strategies. Liang and colleagues establish a high-quality protein expression resource for 8,000 The Cancer Genome Atlas patient samples and 900 Cancer Cell Line Encyclopedia cell lines for approximately 450 proteins, which they use to identify synthetic lethality pairs and metastasis markers.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 10","pages":"1579-1595"},"PeriodicalIF":23.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142126188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.1038/s43018-024-00804-2
Kailan Sierra-Davidson, Genevieve M. Boland
The clinical utility of immune checkpoint inhibitors is limited by immune-related adverse events (irAEs); understanding the mechanisms of irAE development is thus crucial. A study reports that IL-17A-expressing CD4+ T cells were elevated at irAE onset and provides proof of concept for using IL-17A blockade to improve irAEs in two patients.
{"title":"Targeting IL-17A to combat immune-related adverse events","authors":"Kailan Sierra-Davidson, Genevieve M. Boland","doi":"10.1038/s43018-024-00804-2","DOIUrl":"10.1038/s43018-024-00804-2","url":null,"abstract":"The clinical utility of immune checkpoint inhibitors is limited by immune-related adverse events (irAEs); understanding the mechanisms of irAE development is thus crucial. A study reports that IL-17A-expressing CD4+ T cells were elevated at irAE onset and provides proof of concept for using IL-17A blockade to improve irAEs in two patients.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 9","pages":"1289-1291"},"PeriodicalIF":23.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.1038/s43018-024-00810-4
Florentia Dimitriou, Phil F. Cheng, Annalisa Saltari, Katrin Schaper-Gerhardt, Ramon Staeger, Veronika Haunerdinger, Federica Sella, Aizhan Tastanova, Christian Urban, Susanne Dettwiler, Daniela Mihic-Probst, Christian M. Matter, Olivier Michielin, Ralf Gutzmer, Georgina V. Long, Burkhard Becher, Mitchell P. Levesque, Reinhard Dummer
Immune checkpoint inhibitors are standard-of-care for the treatment of advanced melanoma, but their use is limited by immune-related adverse events. Proteomic analyses and multiplex cytokine and chemokine assays from serum at baseline and at the adverse event onset indicated aberrant T cell activity with differential expression of type I and III immune signatures. This was in line with the finding of an increase in the proportion of CD4+ T cells with IL-17A expression at the adverse event onset in the peripheral blood using flow cytometry. Multiplex immunohistochemistry and spatial transcriptomics on immunotherapy-induced skin rash and colitis showed an increase in the proportion of CD4+ T cells with IL-17A expression. Anti-IL-17A was administered in two patients with mild myocarditis, colitis and skin rash with resolution of the adverse events. This study highlights the potential role of type III CD4+ T cells in adverse event development and provides proof-of-principle evidence for a clinical trial using anti-IL-17A for treating adverse events. Dimitriou et al. perform multiomic profiling of patients with melanoma experiencing immunotherapy-associated toxicity and identify a targetable role for type III-associated immune responses with an increase in CD4+ T cells expressing IL-17A.
免疫检查点抑制剂是治疗晚期黑色素瘤的标准药物，但其使用受到免疫相关不良事件的限制。对基线和不良事件发生时的血清进行蛋白质组分析以及多重细胞因子和趋化因子检测表明，T细胞活性异常，I型和III型免疫特征的表达存在差异。这与流式细胞术发现的不良事件发生时外周血中表达 IL-17A 的 CD4+ T 细胞比例增加的结果一致。免疫疗法诱发的皮疹和结肠炎的多重免疫组化和空间转录组学显示，表达 IL-17A 的 CD4+ T 细胞比例增加。两名患有轻度心肌炎、结肠炎和皮疹的患者接受了抗IL-17A治疗，不良反应得到缓解。这项研究强调了 III 型 CD4+ T 细胞在不良事件发生中的潜在作用，并为使用抗 IL-17A 治疗不良事件的临床试验提供了原则性证据。
{"title":"A targetable type III immune response with increase of IL-17A expressing CD4+ T cells is associated with immunotherapy-induced toxicity in melanoma","authors":"Florentia Dimitriou, Phil F. Cheng, Annalisa Saltari, Katrin Schaper-Gerhardt, Ramon Staeger, Veronika Haunerdinger, Federica Sella, Aizhan Tastanova, Christian Urban, Susanne Dettwiler, Daniela Mihic-Probst, Christian M. Matter, Olivier Michielin, Ralf Gutzmer, Georgina V. Long, Burkhard Becher, Mitchell P. Levesque, Reinhard Dummer","doi":"10.1038/s43018-024-00810-4","DOIUrl":"10.1038/s43018-024-00810-4","url":null,"abstract":"Immune checkpoint inhibitors are standard-of-care for the treatment of advanced melanoma, but their use is limited by immune-related adverse events. Proteomic analyses and multiplex cytokine and chemokine assays from serum at baseline and at the adverse event onset indicated aberrant T cell activity with differential expression of type I and III immune signatures. This was in line with the finding of an increase in the proportion of CD4+ T cells with IL-17A expression at the adverse event onset in the peripheral blood using flow cytometry. Multiplex immunohistochemistry and spatial transcriptomics on immunotherapy-induced skin rash and colitis showed an increase in the proportion of CD4+ T cells with IL-17A expression. Anti-IL-17A was administered in two patients with mild myocarditis, colitis and skin rash with resolution of the adverse events. This study highlights the potential role of type III CD4+ T cells in adverse event development and provides proof-of-principle evidence for a clinical trial using anti-IL-17A for treating adverse events. Dimitriou et al. perform multiomic profiling of patients with melanoma experiencing immunotherapy-associated toxicity and identify a targetable role for type III-associated immune responses with an increase in CD4+ T cells expressing IL-17A.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 9","pages":"1390-1408"},"PeriodicalIF":23.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43018-024-00810-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1038/s43018-024-00816-y
Bing Lu, Ru Qiu, Jiatian Wei, Li Wang, Qinkai Zhang, Mingsen Li, Xiudan Zhan, Jian Chen, I-Yun Hsieh, Ciqiu Yang, Jing Zhang, Zicheng Sun, Yifan Zhu, Tao Jiang, Han Zhu, Jie Li, Wei Zhao
How dysregulated liquid–liquid phase separation (LLPS) contributes to the oncogenesis of female triple-negative breast cancer (TNBC) remains unknown. Here we demonstrate that phosphorylated histone deacetylase 6 (phospho-HDAC6) forms LLPS condensates in the nuclei of TNBC cells that are essential for establishing aberrant chromatin architecture. The disordered N-terminal domain and phosphorylated residue of HDAC6 facilitate effective LLPS, whereas nuclear export regions exert a negative dominant effect. Through phase-separation-based screening, we identified Nexturastat A as a specific disruptor of phospho-HDAC6 condensates, which effectively suppresses tumor growth. Mechanistically, importin-β interacts with phospho-HDAC6, promoting its translocation to the nucleus, where 14-3-3θ mediates the condensate formation. Disruption of phospho-HDAC6 LLPS re-established chromatin compartments and topologically associating domain boundaries, leading to disturbed chromatin loops. The phospho-HDAC6-induced aberrant chromatin architecture affects chromatin accessibility, histone acetylation, RNA polymerase II elongation and transcriptional profiles in TNBC. This study demonstrates phospho-HDAC6 LLPS as an emerging mechanism underlying the dysregulation of chromatin architecture in TNBC. Lu et al. investigate the involvement of liquid–liquid phase separation in the progression of triple-negative breast cancer and find that phosphorylated histone deacetylase 6 forms condensates that affect chromatin accessibility and oncogenic transcriptional programs.
{"title":"Phase separation of phospho-HDAC6 drives aberrant chromatin architecture in triple-negative breast cancer","authors":"Bing Lu, Ru Qiu, Jiatian Wei, Li Wang, Qinkai Zhang, Mingsen Li, Xiudan Zhan, Jian Chen, I-Yun Hsieh, Ciqiu Yang, Jing Zhang, Zicheng Sun, Yifan Zhu, Tao Jiang, Han Zhu, Jie Li, Wei Zhao","doi":"10.1038/s43018-024-00816-y","DOIUrl":"10.1038/s43018-024-00816-y","url":null,"abstract":"How dysregulated liquid–liquid phase separation (LLPS) contributes to the oncogenesis of female triple-negative breast cancer (TNBC) remains unknown. Here we demonstrate that phosphorylated histone deacetylase 6 (phospho-HDAC6) forms LLPS condensates in the nuclei of TNBC cells that are essential for establishing aberrant chromatin architecture. The disordered N-terminal domain and phosphorylated residue of HDAC6 facilitate effective LLPS, whereas nuclear export regions exert a negative dominant effect. Through phase-separation-based screening, we identified Nexturastat A as a specific disruptor of phospho-HDAC6 condensates, which effectively suppresses tumor growth. Mechanistically, importin-β interacts with phospho-HDAC6, promoting its translocation to the nucleus, where 14-3-3θ mediates the condensate formation. Disruption of phospho-HDAC6 LLPS re-established chromatin compartments and topologically associating domain boundaries, leading to disturbed chromatin loops. The phospho-HDAC6-induced aberrant chromatin architecture affects chromatin accessibility, histone acetylation, RNA polymerase II elongation and transcriptional profiles in TNBC. This study demonstrates phospho-HDAC6 LLPS as an emerging mechanism underlying the dysregulation of chromatin architecture in TNBC. Lu et al. investigate the involvement of liquid–liquid phase separation in the progression of triple-negative breast cancer and find that phosphorylated histone deacetylase 6 forms condensates that affect chromatin accessibility and oncogenic transcriptional programs.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 11","pages":"1622-1640"},"PeriodicalIF":23.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43018-024-00816-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142093562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1038/s43018-024-00818-w
Shambavi Richard, Alexander M. Lesokhin, Barry Paul, Jonathan L. Kaufman, Matthew Pianko, Noa Biran, Ravi Vij, Deon B. Doxie, Maryam I. Azeem, Mercedes Martillo, Katie Wozniak, Hearn J. Cho, Kavita M. Dhodapkar, Madhav V. Dhodapkar
Persons with myeloma were randomized to receive an anti-TIGIT (T cell immunoreceptor) or anti-LAG3 (lymphocyte activation gene) antibody followed by combination with pomalidomide and dexamethasone ( NCT04150965 ). Primary and secondary endpoints were safety and efficacy, respectively. Therapy was well tolerated without dose-limiting toxicity. Durable clinical responses were observed in both the anti-TIGIT(three of six participants) and the anti-LAG3 (two of six participants) arms. Anti-LAG3 responders had higher naive cluster of differentiation 4 (CD4)-positive T cells and lower programmed cell death protein 1-positive effector T cells. Anti-TIGIT responders had higher CD226 expression, natural killer cell activation and lower CD112 expression. These data demonstrate the clinical activity of TIGIT–LAG3 blockade and identify pathway-specific response correlates in myeloma. Richard et al. perform a clinical trial of anti-TIGIT (T cell immunoreceptor) or anti-LAG3 (lymphocyte activation gene) antibody in combination with pomalidomide and dexamethasone in persons with multiple myeloma and define correlates of response using mass cytometry.
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