Pub Date : 2024-10-28DOI: 10.1038/s41392-024-02015-8
Florian R. Greten, Melek C. Arkan
A recent study published in Nature by Roje, Zhang and colleagues highlights the emergent role gut microbiota play in processing environmental carcinogens and raises its potential as a target for reducing cancer risk in humans.1 This study fills yet another piece into the giant jigsaw puzzle that illustrates the central role of the dynamic structure and function of the intestinal microbiome in cancer pathogenesis and therapy efficacy.
{"title":"Gut microbial carcinogen metabolism: another avenue to cancer","authors":"Florian R. Greten, Melek C. Arkan","doi":"10.1038/s41392-024-02015-8","DOIUrl":"https://doi.org/10.1038/s41392-024-02015-8","url":null,"abstract":"<p>A recent study published in <i>Nature</i> by Roje, Zhang and colleagues highlights the emergent role gut microbiota play in processing environmental carcinogens and raises its potential as a target for reducing cancer risk in humans.<sup>1</sup> This study fills yet another piece into the giant jigsaw puzzle that illustrates the central role of the dynamic structure and function of the intestinal microbiome in cancer pathogenesis and therapy efficacy.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142519236","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 : 2024-10-28DOI: 10.1038/s41392-024-02010-z
Nariaki Asada, Christian F. Krebs, Ulf Panzer
In a landmark study recently published in Cell, Berger et al. demonstrated that computationally designed miniproteins could serve as novel, orally available treatment strategies by specifically targeting cytokine signaling pathways through the potent inhibition of ligand-receptor interactions in the body.1 This breakthrough study unveils the potential for miniprotein-based therapies to revolutionize molecular treatment strategies for autoimmune diseases and cancers.
{"title":"Miniproteins may have a big impact: new therapeutics for autoimmune diseases and beyond","authors":"Nariaki Asada, Christian F. Krebs, Ulf Panzer","doi":"10.1038/s41392-024-02010-z","DOIUrl":"https://doi.org/10.1038/s41392-024-02010-z","url":null,"abstract":"<p>In a landmark study recently published in <i>Cell</i>, Berger et al. demonstrated that computationally designed miniproteins could serve as novel, orally available treatment strategies by specifically targeting cytokine signaling pathways through the potent inhibition of ligand-receptor interactions in the body.<sup>1</sup> This breakthrough study unveils the potential for miniprotein-based therapies to revolutionize molecular treatment strategies for autoimmune diseases and cancers.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142519238","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 : 2024-10-28DOI: 10.1038/s41392-024-01992-0
Hongtao Duan, Changjian Shao, Zhilin Luo, Tianhu Wang, Liping Tong, Honggang Liu, Xin Yao, Jie Lei, Jinbo Zhao, Yuan Gao, Tao Jiang, Xiaolong Yan
This open-label, single-arm, phase 2 trial evaluated the efficacy and safety of neoadjuvant sintilimab combined with anlotinib and chemotherapy, followed by adjuvant sintilimab, for resectable NSCLC. Forty-five patients received anlotinib (10 mg, QD, PO, days 1–14), sintilimab (200 mg, day 1), and platinum-based chemotherapy of each three-week cycle for 3 cycles, followed by surgery within 4–6 weeks. Adjuvant sintilimab (200 mg) was administered every 3 weeks. The primary endpoint was achieving a pathological complete response (pCR). From June 10, 2021 through October 10, 2023, 45 patients were enrolled and composed the intention-to-treat population. Twenty-six patients (57.8%) achieved pCR, and 30 (66.7%) achieved major pathological response (MPR). Forty-one patients underwent surgery. In the per-protocol set (PP set), 63.4% (26/41) achieved pCR, and 73.2% achieved MPR. The median event-free survival was not attained (95% CI, 25.1-NE). During the neoadjuvant treatment phase, grade 3 or 4 treatment-related adverse events were observed in 25 patients (55.6%), while immune-related adverse events were reported in 7 patients (15.6%). We assessed vascular normalization and infiltration of immune-related cells by detecting the expression of relevant cell markers in NSCLC tissues with mIHC. Significant tumor microenvironment changes were observed in pCR patients, including reduced VEGF+ cells and CD4+Foxp3+ Treg cells, and increased perivascular CD4+ T cells, CD39+CD8+ T cells, and M1 macrophages. In conclusion, perioperative sintilimab and neoadjuvant anlotinib plus chemotherapy achieved pCR in a notable proportion of patients with resectable NSCLC and were associated with profound changes in the tumour microenvironment (ClinicalTrials.gov NCT05400070).
{"title":"Perioperative sintilimab and neoadjuvant anlotinib plus chemotherapy for resectable non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 2 trial (TD-NeoFOUR trial)","authors":"Hongtao Duan, Changjian Shao, Zhilin Luo, Tianhu Wang, Liping Tong, Honggang Liu, Xin Yao, Jie Lei, Jinbo Zhao, Yuan Gao, Tao Jiang, Xiaolong Yan","doi":"10.1038/s41392-024-01992-0","DOIUrl":"https://doi.org/10.1038/s41392-024-01992-0","url":null,"abstract":"<p>This open-label, single-arm, phase 2 trial evaluated the efficacy and safety of neoadjuvant sintilimab combined with anlotinib and chemotherapy, followed by adjuvant sintilimab, for resectable NSCLC. Forty-five patients received anlotinib (10 mg, QD, PO, days 1–14), sintilimab (200 mg, day 1), and platinum-based chemotherapy of each three-week cycle for 3 cycles, followed by surgery within 4–6 weeks. Adjuvant sintilimab (200 mg) was administered every 3 weeks. The primary endpoint was achieving a pathological complete response (pCR). From June 10, 2021 through October 10, 2023, 45 patients were enrolled and composed the intention-to-treat population. Twenty-six patients (57.8%) achieved pCR, and 30 (66.7%) achieved major pathological response (MPR). Forty-one patients underwent surgery. In the per-protocol set (PP set), 63.4% (26/41) achieved pCR, and 73.2% achieved MPR. The median event-free survival was not attained (95% CI, 25.1-NE). During the neoadjuvant treatment phase, grade 3 or 4 treatment-related adverse events were observed in 25 patients (55.6%), while immune-related adverse events were reported in 7 patients (15.6%). We assessed vascular normalization and infiltration of immune-related cells by detecting the expression of relevant cell markers in NSCLC tissues with mIHC. Significant tumor microenvironment changes were observed in pCR patients, including reduced VEGF<sup>+</sup> cells and CD4<sup>+</sup>Foxp3<sup>+</sup> Treg cells, and increased perivascular CD4<sup>+</sup> T cells, CD39<sup>+</sup>CD8<sup>+</sup> T cells, and M1 macrophages. In conclusion, perioperative sintilimab and neoadjuvant anlotinib plus chemotherapy achieved pCR in a notable proportion of patients with resectable NSCLC and were associated with profound changes in the tumour microenvironment (ClinicalTrials.gov NCT05400070).</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490963","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 : 2024-10-23DOI: 10.1038/s41392-024-01988-w
Sai-Wei Huang, Wei Jiang, Sha Xu, Yuan Zhang, Juan Du, Ya-Qin Wang, Kun-Yu Yang, Ning Zhang, Fang Liu, Guo-Rong Zou, Feng Jin, Hai-Jun Wu, Yang-Ying Zhou, Xiao-Dong Zhu, Nian-Yong Chen, Cheng Xu, Han Qiao, Na Liu, Ying Sun, Jun Ma, Ye-Lin Liang, Xu Liu
The identification of predictors for immunotherapy is often hampered by the absence of control groups in many studies, making it difficult to distinguish between prognostic and predictive biomarkers. This study presents biomarker analyses from the phase 3 CONTINUUM trial (NCT03700476), the first to show that adding anti-PD-1 (aPD1) to chemoradiotherapy (CRT) improves event-free survival (EFS) in patients with locoregionally advanced nasopharyngeal carcinoma. A dynamic single-cell atlas was profiled using mass cytometry on peripheral blood mononuclear cell samples from 12 pairs of matched relapsing and non-relapsing patients in the aPD1-CRT arm. Using a supervised representation learning algorithm, we identified a Ki67+ proliferating regulatory T cells (Tregs) population expressing high levels of activated and immunosuppressive molecules including FOXP3, CD38, HLA-DR, CD39, and PD-1, whose abundance correlated with treatment outcome. The frequency of these Ki67+ Tregs was significantly higher at baseline and increased during treatment in patients who relapsed compared to non-relapsers. Further validation through flow cytometry (n = 120) confirmed the predictive value of this Treg subset. Multiplex immunohistochemistry (n = 249) demonstrated that Ki67+ Tregs in tumors could predict immunotherapy benefit, with aPD1 improving EFS only in patients with low baseline levels of Ki67+ Tregs. These findings were further validated in the multicenter phase 3 DIPPER trial (n = 262, NCT03427827) and the phase 3 OAK trial of anti-PD-L1 immunotherapy in NSCLC, underscoring the predictive value of Ki67+ Treg frequency in identifying the beneficiaries of immunotherapy and potentially guiding personalized treatment strategies.
{"title":"Systemic longitudinal immune profiling identifies proliferating Treg cells as predictors of immunotherapy benefit: biomarker analysis from the phase 3 CONTINUUM and DIPPER trials","authors":"Sai-Wei Huang, Wei Jiang, Sha Xu, Yuan Zhang, Juan Du, Ya-Qin Wang, Kun-Yu Yang, Ning Zhang, Fang Liu, Guo-Rong Zou, Feng Jin, Hai-Jun Wu, Yang-Ying Zhou, Xiao-Dong Zhu, Nian-Yong Chen, Cheng Xu, Han Qiao, Na Liu, Ying Sun, Jun Ma, Ye-Lin Liang, Xu Liu","doi":"10.1038/s41392-024-01988-w","DOIUrl":"https://doi.org/10.1038/s41392-024-01988-w","url":null,"abstract":"<p>The identification of predictors for immunotherapy is often hampered by the absence of control groups in many studies, making it difficult to distinguish between prognostic and predictive biomarkers. This study presents biomarker analyses from the phase 3 CONTINUUM trial (NCT03700476), the first to show that adding anti-PD-1 (aPD1) to chemoradiotherapy (CRT) improves event-free survival (EFS) in patients with locoregionally advanced nasopharyngeal carcinoma. A dynamic single-cell atlas was profiled using mass cytometry on peripheral blood mononuclear cell samples from 12 pairs of matched relapsing and non-relapsing patients in the aPD1-CRT arm. Using a supervised representation learning algorithm, we identified a Ki67<sup>+</sup> proliferating regulatory T cells (Tregs) population expressing high levels of activated and immunosuppressive molecules including FOXP3, CD38, HLA-DR, CD39, and PD-1, whose abundance correlated with treatment outcome. The frequency of these Ki67<sup>+</sup> Tregs was significantly higher at baseline and increased during treatment in patients who relapsed compared to non-relapsers. Further validation through flow cytometry (<i>n</i> = 120) confirmed the predictive value of this Treg subset. Multiplex immunohistochemistry (<i>n</i> = 249) demonstrated that Ki67<sup>+</sup> Tregs in tumors could predict immunotherapy benefit, with aPD1 improving EFS only in patients with low baseline levels of Ki67<sup>+</sup> Tregs. These findings were further validated in the multicenter phase 3 DIPPER trial (<i>n</i> = 262, NCT03427827) and the phase 3 OAK trial of anti-PD-L1 immunotherapy in NSCLC, underscoring the predictive value of Ki67<sup>+</sup> Treg frequency in identifying the beneficiaries of immunotherapy and potentially guiding personalized treatment strategies.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486722","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}
Newly diagnosed patients with high-risk acute graft-versus-host disease (aGVHD) often experience poor clinical outcomes and low complete remission rates. Ruxolitinib with corticosteroids showed promising efficacy in improving response and failure free survival in our phase I study. This study (ClinicalTrials.gov: NCT04061876) sought to evaluate the safety and effectiveness of combining ruxolitinib (RUX, 5 mg/day) with corticosteroids (1 mg/kg/day methylprednisolone, RUX/steroids combined group) versus using methylprednisolone alone (2 mg/kg/day, steroids-only group). Newly diagnosed patients with intermediate- or high-risk aGVHD were included, with risk levels classified by either the Minnesota aGVHD Risk Score or biomarker assessment. Patients were randomized in a ratio of 1:1 into 2 groups: 99 patients received RUX combined with methylprednisolone, while the other 99 received methylprednisolone alone as the initial treatment. The RUX/steroids group showed a significantly higher overall response rate (ORR) on day 28 (92.9%) compared to the steroids-only group (70.7%, Odds Ratio [OR] = 5.8; 95% Confidence Interval [CI], 2.4–14.0; P < 0.001). Similarly, the ORR on day 56 was higher in the RUX/steroids group (85.9% vs. 46.5%; OR = 7.07; 95% CI, 3.36–15.75; P < 0.001). Additionally, the 18-month failure-free survival was significantly better in the RUX/steroids group (57.2%) compared to the steroids-only group (33.3%; Hazard Ratio = 0.46; 95% CI, 0.31–0.68; P < 0.001). Adverse events (AEs) frequencies were comparable between both groups, with the exception of fewer grade 4 AEs in the RUX/steroids group (26.3% vs. 50.5% P = 0.005). To our knowledge, this study is the first prospective, randomized controlled trial to demonstrate that adding ruxolitinib to the standard methylprednisolone regimen provides an effective and safe first-line treatment for newly diagnosed high-risk acute GVHD.
新确诊的高危急性移植物抗宿主病(aGVHD)患者往往临床疗效不佳,完全缓解率低。在我们的 I 期研究中,Ruxolitinib 联合皮质类固醇治疗在改善反应和无失败生存期方面显示出良好的疗效。这项研究(ClinicalTrials.gov:NCT04061876)旨在评估Ruxolitinib(RUX,5毫克/天)与皮质类固醇(1毫克/公斤/天甲基强的松龙,RUX/皮质类固醇联合组)联合治疗与单独使用甲基强的松龙(2毫克/公斤/天,仅使用皮质类固醇组)的安全性和有效性。新确诊的中危或高危 aGVHD 患者均被纳入其中,风险等级根据明尼苏达 aGVHD 风险评分或生物标志物评估进行分类。患者按1:1的比例随机分为两组:99名患者接受RUX联合甲基强的松龙治疗,另外99名患者则接受单纯甲基强的松龙作为初始治疗。RUX/类固醇组第28天的总反应率(ORR)(92.9%)明显高于单纯类固醇组(70.7%,Odds Ratio [OR] = 5.8; 95% Confidence Interval [CI], 2.4-14.0; P < 0.001)。同样,RUX/类固醇组第56天的ORR也更高(85.9% vs. 46.5%;OR = 7.07;95% CI, 3.36-15.75; P <0.001)。此外,与单纯类固醇组(33.3%;危险比=0.46;95% CI,0.31-0.68;P <0.001)相比,RUX/类固醇组的18个月无失败生存率(57.2%)明显更高。两组的不良事件(AEs)发生率相当,但RUX/类固醇组的4级不良事件较少(26.3% vs. 50.5% P = 0.005)。据我们所知,该研究是首个前瞻性随机对照试验,证明在标准甲泼尼龙方案中加入鲁索利替尼可为新诊断的高危急性GVHD患者提供有效、安全的一线治疗。
{"title":"Ruxolitinib plus steroids for acute graft versus host disease: a multicenter, randomized, phase 3 trial","authors":"Liping Dou, Yanli Zhao, Jingjing Yang, Lei Deng, Nan Wang, Xiawei Zhang, Qingyang Liu, Yan Yang, Zhijie Wei, Fuxu Wang, Yifan Jiao, Fei Li, Songhua Luan, Liangding Hu, Sujun Gao, Chuanfang Liu, Xiangjun Liu, Jinsong Yan, Xuejun Zhang, Fang Zhou, Peihua Lu, Daihong Liu","doi":"10.1038/s41392-024-01987-x","DOIUrl":"https://doi.org/10.1038/s41392-024-01987-x","url":null,"abstract":"<p>Newly diagnosed patients with high-risk acute graft-versus-host disease (aGVHD) often experience poor clinical outcomes and low complete remission rates. Ruxolitinib with corticosteroids showed promising efficacy in improving response and failure free survival in our phase I study. This study (ClinicalTrials.gov: NCT04061876) sought to evaluate the safety and effectiveness of combining ruxolitinib (RUX, 5 mg/day) with corticosteroids (1 mg/kg/day methylprednisolone, RUX/steroids combined group) versus using methylprednisolone alone (2 mg/kg/day, steroids-only group). Newly diagnosed patients with intermediate- or high-risk aGVHD were included, with risk levels classified by either the Minnesota aGVHD Risk Score or biomarker assessment. Patients were randomized in a ratio of 1:1 into 2 groups: 99 patients received RUX combined with methylprednisolone, while the other 99 received methylprednisolone alone as the initial treatment. The RUX/steroids group showed a significantly higher overall response rate (ORR) on day 28 (92.9%) compared to the steroids-only group (70.7%, Odds Ratio [OR] = 5.8; 95% Confidence Interval [CI], 2.4–14.0; <i>P</i> < 0.001). Similarly, the ORR on day 56 was higher in the RUX/steroids group (85.9% vs. 46.5%; OR = 7.07; 95% CI, 3.36–15.75; <i>P</i> < 0.001). Additionally, the 18-month failure-free survival was significantly better in the RUX/steroids group (57.2%) compared to the steroids-only group (33.3%; Hazard Ratio = 0.46; 95% CI, 0.31–0.68; <i>P</i> < 0.001). Adverse events (AEs) frequencies were comparable between both groups, with the exception of fewer grade 4 AEs in the RUX/steroids group (26.3% vs. 50.5% <i>P</i> = 0.005). To our knowledge, this study is the first prospective, randomized controlled trial to demonstrate that adding ruxolitinib to the standard methylprednisolone regimen provides an effective and safe first-line treatment for newly diagnosed high-risk acute GVHD.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486723","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 : 2024-10-23DOI: 10.1038/s41392-024-02016-7
Dharmendra Kumar, Iqbal Hyder, Wilfried A. Kues
In a landmark study published in Cell, Parasyraki et al. demonstrated a functional role of 5-formylcytosine (5fC) as an epigenetic mark during zygotic/embryonic genome activation (ZGA) in Xenopus and murine embryos that is spatially associated with RNA polymerase III (Pol III) transcription.1 ZGA (or maternal to embryonic transition) is the unique phase of embryonic development when the maternal genome of the oocyte is reprogrammed to an embryonic gene expression.
{"title":"5-Formylcytosine: a new epigenetic player","authors":"Dharmendra Kumar, Iqbal Hyder, Wilfried A. Kues","doi":"10.1038/s41392-024-02016-7","DOIUrl":"https://doi.org/10.1038/s41392-024-02016-7","url":null,"abstract":"<p>In a landmark study published in <i>Cell</i>, Parasyraki et al. demonstrated a functional role of 5-formylcytosine (5fC) as an epigenetic mark during zygotic/embryonic genome activation (ZGA) in <i>Xenopus</i> and murine embryos that is spatially associated with RNA polymerase III (Pol III) transcription.<sup>1</sup> ZGA (or maternal to embryonic transition) is the unique phase of embryonic development when the maternal genome of the oocyte is reprogrammed to an embryonic gene expression.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487284","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}
Clinical evidence supports the notion that T cell exhaustion and terminal differentiation pose challenges to the persistence and effectiveness of chimeric antigen receptor-T (CAR-T) cells. MEK1/2 inhibitors (MEKIs), widely used in cancer treatment due to their ability to inhibit aberrant MAPK signaling, have shown potential synergistic effects when combined with immunotherapy. However, the impact and mechanisms of MEKIs on CAR-T cells remain uncertain and controversial. To address this, we conducted a comprehensive investigation to determine whether MEKIs enhance or impair the efficacy of CAR-T cells. Our findings revealed that MEKIs attenuated CAR-T cell exhaustion and terminal differentiation induced by tonic signaling and antigen stimulation, thereby improving CAR-T cell efficacy against hematological and solid tumors. Remarkably, these effects were independent of the specific scFvs and costimulatory domains utilized in CARs. Mechanistically, analysis of bulk and single-cell transcriptional profiles demonstrates that the effect of MEK inhibition was related to diminish anabolic metabolism and downregulation of c-Fos and JunB. Additionally, the overexpression of c-Fos or JunB in CAR-T cells counteracted the effects of MEK inhibition. Furthermore, our Cut-and-Tag assay revealed that MEK inhibition downregulated the JunB-driven gene profiles associated with exhaustion, differentiation, anergy, glycolysis, and apoptosis. In summary, our research unveil the critical role of the MAPK-c-Fos-JunB axis in driving CAR-T cell exhaustion and terminal differentiation. These mechanistic insights significantly broaden the potential application of MEKIs to enhance the effectiveness of CAR-T therapy.
{"title":"MEK inhibition prevents CAR-T cell exhaustion and differentiation via downregulation of c-Fos and JunB","authors":"Xiujian Wang, Xiao Tao, Pengjie Chen, Penglei Jiang, Wenxiao Li, Hefeng Chang, Cong Wei, Xinyi Lai, Hao Zhang, Yihan Pan, Lijuan Ding, Zuyu Liang, Jiazhen Cui, Mi Shao, Xinyi Teng, Tianning Gu, Jieping Wei, Delin Kong, Xiaohui Si, Yingli Han, Huarui Fu, Yu Lin, Jian Yu, Xia Li, Dongrui Wang, Yongxian Hu, Pengxu Qian, He Huang","doi":"10.1038/s41392-024-01986-y","DOIUrl":"https://doi.org/10.1038/s41392-024-01986-y","url":null,"abstract":"<p>Clinical evidence supports the notion that T cell exhaustion and terminal differentiation pose challenges to the persistence and effectiveness of chimeric antigen receptor-T (CAR-T) cells. MEK1/2 inhibitors (MEKIs), widely used in cancer treatment due to their ability to inhibit aberrant MAPK signaling, have shown potential synergistic effects when combined with immunotherapy. However, the impact and mechanisms of MEKIs on CAR-T cells remain uncertain and controversial. To address this, we conducted a comprehensive investigation to determine whether MEKIs enhance or impair the efficacy of CAR-T cells. Our findings revealed that MEKIs attenuated CAR-T cell exhaustion and terminal differentiation induced by tonic signaling and antigen stimulation, thereby improving CAR-T cell efficacy against hematological and solid tumors. Remarkably, these effects were independent of the specific scFvs and costimulatory domains utilized in CARs. Mechanistically, analysis of bulk and single-cell transcriptional profiles demonstrates that the effect of MEK inhibition was related to diminish anabolic metabolism and downregulation of c-Fos and JunB. Additionally, the overexpression of c-Fos or JunB in CAR-T cells counteracted the effects of MEK inhibition. Furthermore, our Cut-and-Tag assay revealed that MEK inhibition downregulated the JunB-driven gene profiles associated with exhaustion, differentiation, anergy, glycolysis, and apoptosis. In summary, our research unveil the critical role of the MAPK-c-Fos-JunB axis in driving CAR-T cell exhaustion and terminal differentiation. These mechanistic insights significantly broaden the potential application of MEKIs to enhance the effectiveness of CAR-T therapy.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486724","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}
Granulomatous lobular mastitis (GLM) is a chronic idiopathic granulomatous mastitis of the mammary gland characterized by significant pain and a high propensity for recurrence, the incidence rate has gradually increased, and has become a serious breast disease that should not be ignored. GLM is highly suspected relative to microbial infections, especially those of Corynebacterium species; however, the mechanisms involved are unclear, and prevention and treatment are difficult. In this study, we demonstrated the pathogenicity of Corynebacterium parakroppenstedtii in GLM using Koch’s postulates. Based on the drug sensitization results of C. parakroppenstedtii, and utilizing a retrospective study in conjunction with a comprehensive literature review, we suggested an efficacious, targeted antibiotic treatment strategy for GLM. Subsequently, we identified the pathogenic factor as a new type of glycolipid (named corynekropbactins) secreted by C. parakroppenstedtii. Corynekropbactins may chelate iron, cause the death of mammary cells and other mammary -gland-colonizing bacteria, and increase the levels of inflammatory cytokines. We further analyzed the prevalence of C. parakroppenstedtii infection in patients with GLM. Finally, we suggested that the lipophilicity of C. parakroppenstedtii may be associated with its infection route and proposed a possible model for the development of GLM. This research holds significant implications for the clinical diagnosis and therapeutic management of GLM, offering new insights into targeted treatment approaches.
{"title":"Corynebacterium parakroppenstedtii secretes a novel glycolipid to promote the development of granulomatous lobular mastitis","authors":"Ran Liu, Zixuan Luo, Chong Dai, Yuchen Wei, Shuqing Yan, Xinwen Kuang, Kuan Qi, Aisi Fu, Yinxin Li, Shuai Fu, Zhengning Ma, Wen Dai, Xiao Xiao, Qing Wu, Haokui Zhou, Yan Rao, Jingping Yuan, Ting Shi, Zixin Deng, Chuang Chen, Tiangang Liu","doi":"10.1038/s41392-024-01984-0","DOIUrl":"https://doi.org/10.1038/s41392-024-01984-0","url":null,"abstract":"<p>Granulomatous lobular mastitis (GLM) is a chronic idiopathic granulomatous mastitis of the mammary gland characterized by significant pain and a high propensity for recurrence, the incidence rate has gradually increased, and has become a serious breast disease that should not be ignored. GLM is highly suspected relative to microbial infections, especially those of <i>Corynebacterium</i> species; however, the mechanisms involved are unclear, and prevention and treatment are difficult. In this study, we demonstrated the pathogenicity of <i>Corynebacterium parakroppenstedtii</i> in GLM using Koch’s postulates. Based on the drug sensitization results of <i>C. parakroppenstedtii</i>, and utilizing a retrospective study in conjunction with a comprehensive literature review, we suggested an efficacious, targeted antibiotic treatment strategy for GLM. Subsequently, we identified the pathogenic factor as a new type of glycolipid (named corynekropbactins) secreted by <i>C. parakroppenstedtii</i>. Corynekropbactins may chelate iron, cause the death of mammary cells and other mammary -gland-colonizing bacteria, and increase the levels of inflammatory cytokines. We further analyzed the prevalence of <i>C. parakroppenstedtii</i> infection in patients with GLM. Finally, we suggested that the lipophilicity of <i>C. parakroppenstedtii</i> may be associated with its infection route and proposed a possible model for the development of GLM. This research holds significant implications for the clinical diagnosis and therapeutic management of GLM, offering new insights into targeted treatment approaches.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451590","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}
PROteolysis TArgeting Chimeras (PROTACs) have been considered the next blockbuster therapies. However, due to their inherent limitations, the efficacy of PROTACs is frequently impaired by limited tissue penetration and particularly insufficient cellular internalization into their action sites. Herein, based on the ultra-pH-sensitive and enzyme-sensitive nanotechnology, a type of polymer PROTAC conjugated and pH/cathepsin B sequential responsive nanoparticles (PSRNs) are deliberately designed, following the construction of the PROTAC for Cyclin-dependent kinase 4 and 6 (CDK4/6). Colorectal cancer (CRC) which hardly responds to many treatments even immune checkpoint blockades was selected as the tumor model in this study. As a result, PSRNs were found to maintain nanostructure (40 nm) in circulation and efficiently accumulated in tumors via enhanced permeation and retention effect. Then, they were dissociated into unimers (<10 nm) in response to an acidic tumor microenvironment, facilitating tumor penetration and cellular internalization. Eventually, the CDK4/6 degrading PROTACs were released intracellularly following the cleavage of cathepsin B. Importantly, PSRNs led to the enhanced degradation of target protein in vitro and in vivo. The degradation of CDK4/6 also augmented the efficacy of immune checkpoint blockades, through the upregulation of programmed cell death-ligand 1 (PD-L1) expression in cancer cells and the suppression of regulatory T cells cell proliferation in tumor microenvironment. By combination with α-PD-1, an enhanced anti-tumor outcome is well achieved in CT26 tumor model. Overall, our study verifies the significance of precise intracellular delivery of PROTACs and introduces a promising therapeutic strategy for the targeted combination treatment of CRC.
{"title":"Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy","authors":"Liuqing Yang, Ye Yang, Jing Zhang, Minghui Li, Long Yang, Xing Wang, Meifang Chen, Hua Zhang, Bing He, Xueqing Wang, Wenbing Dai, Yiguang Wang, Qiang Zhang","doi":"10.1038/s41392-024-01983-1","DOIUrl":"https://doi.org/10.1038/s41392-024-01983-1","url":null,"abstract":"<p>PROteolysis TArgeting Chimeras (PROTACs) have been considered the next blockbuster therapies. However, due to their inherent limitations, the efficacy of PROTACs is frequently impaired by limited tissue penetration and particularly insufficient cellular internalization into their action sites. Herein, based on the ultra-pH-sensitive and enzyme-sensitive nanotechnology, a type of polymer PROTAC conjugated and pH/cathepsin B sequential responsive nanoparticles (PSRNs) are deliberately designed, following the construction of the PROTAC for Cyclin-dependent kinase 4 and 6 (CDK4/6). Colorectal cancer (CRC) which hardly responds to many treatments even immune checkpoint blockades was selected as the tumor model in this study. As a result, PSRNs were found to maintain nanostructure (40 nm) in circulation and efficiently accumulated in tumors via enhanced permeation and retention effect. Then, they were dissociated into unimers (<10 nm) in response to an acidic tumor microenvironment, facilitating tumor penetration and cellular internalization. Eventually, the CDK4/6 degrading PROTACs were released intracellularly following the cleavage of cathepsin B. Importantly, PSRNs led to the enhanced degradation of target protein in vitro and in vivo. The degradation of CDK4/6 also augmented the efficacy of immune checkpoint blockades, through the upregulation of programmed cell death-ligand 1 (PD-L1) expression in cancer cells and the suppression of regulatory T cells cell proliferation in tumor microenvironment. By combination with α-PD-1, an enhanced anti-tumor outcome is well achieved in CT26 tumor model. Overall, our study verifies the significance of precise intracellular delivery of PROTACs and introduces a promising therapeutic strategy for the targeted combination treatment of CRC.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448209","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 : 2024-10-18DOI: 10.1038/s41392-024-01979-x
Bo Wu, Bo Zhang, Bowen Li, Haoqi Wu, Meixi Jiang
Immunotherapy has made significant strides in cancer treatment, particularly through immune checkpoint blockade (ICB), which has shown notable clinical benefits across various tumor types. Despite the transformative impact of ICB treatment in cancer therapy, only a minority of patients exhibit a positive response to it. In patients with solid tumors, those who respond well to ICB treatment typically demonstrate an active immune profile referred to as the “hot” (immune-inflamed) phenotype. On the other hand, non-responsive patients may exhibit a distinct “cold” (immune-desert) phenotype, differing from the features of “hot” tumors. Additionally, there is a more nuanced “excluded” immune phenotype, positioned between the “cold” and “hot” categories, known as the immune “excluded” type. Effective differentiation between “cold” and “hot” tumors, and understanding tumor intrinsic factors, immune characteristics, TME, and external factors are critical for predicting tumor response and treatment results. It is widely accepted that ICB therapy exerts a more profound effect on “hot” tumors, with limited efficacy against “cold” or “altered” tumors, necessitating combinations with other therapeutic modalities to enhance immune cell infiltration into tumor tissue and convert “cold” or “altered” tumors into “hot” ones. Therefore, aligning with the traits of “cold” and “hot” tumors, this review systematically delineates the respective immune characteristics, influencing factors, and extensively discusses varied treatment approaches and drug targets based on “cold” and “hot” tumors to assess clinical efficacy.
{"title":"Cold and hot tumors: from molecular mechanisms to targeted therapy","authors":"Bo Wu, Bo Zhang, Bowen Li, Haoqi Wu, Meixi Jiang","doi":"10.1038/s41392-024-01979-x","DOIUrl":"https://doi.org/10.1038/s41392-024-01979-x","url":null,"abstract":"<p>Immunotherapy has made significant strides in cancer treatment, particularly through immune checkpoint blockade (ICB), which has shown notable clinical benefits across various tumor types. Despite the transformative impact of ICB treatment in cancer therapy, only a minority of patients exhibit a positive response to it. In patients with solid tumors, those who respond well to ICB treatment typically demonstrate an active immune profile referred to as the “hot” (immune-inflamed) phenotype. On the other hand, non-responsive patients may exhibit a distinct “cold” (immune-desert) phenotype, differing from the features of “hot” tumors. Additionally, there is a more nuanced “excluded” immune phenotype, positioned between the “cold” and “hot” categories, known as the immune “excluded” type. Effective differentiation between “cold” and “hot” tumors, and understanding tumor intrinsic factors, immune characteristics, TME, and external factors are critical for predicting tumor response and treatment results. It is widely accepted that ICB therapy exerts a more profound effect on “hot” tumors, with limited efficacy against “cold” or “altered” tumors, necessitating combinations with other therapeutic modalities to enhance immune cell infiltration into tumor tissue and convert “cold” or “altered” tumors into “hot” ones. Therefore, aligning with the traits of “cold” and “hot” tumors, this review systematically delineates the respective immune characteristics, influencing factors, and extensively discusses varied treatment approaches and drug targets based on “cold” and “hot” tumors to assess clinical efficacy.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448208","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}