Pub Date : 2024-12-26DOI: 10.1016/j.drup.2024.101198
Hyung-Min Ahn , Seog-Yun Park , Yura Choi , Jaemin Kim , Youngjoo Lee
Tarlatamab, a novel bispecific T-cell engager, has demonstrated unprecedented efficacy in patients with small cell lung cancer. However, there is no known mechanism of resistance to tarlatamab. This study suggests that a transcriptional expression shift might be associated with acquired resistance to tarlatamab.
{"title":"Molecular subtype changes after acquiring resistance to tarlatamab in small cell lung cancer","authors":"Hyung-Min Ahn , Seog-Yun Park , Yura Choi , Jaemin Kim , Youngjoo Lee","doi":"10.1016/j.drup.2024.101198","DOIUrl":"10.1016/j.drup.2024.101198","url":null,"abstract":"<div><div>Tarlatamab, a novel bispecific T-cell engager, has demonstrated unprecedented efficacy in patients with small cell lung cancer. However, there is no known mechanism of resistance to tarlatamab. This study suggests that a transcriptional expression shift might be associated with acquired resistance to tarlatamab.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101198"},"PeriodicalIF":15.8,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142916197","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 : 2024-12-26DOI: 10.1016/j.drup.2024.101197
Weiguo Xu , Bin Zhou , Ping Wang , Yuyan Ma , Yu Jiang , Dongping Mo , Jun Wu , Jingjing Ma , Xiao Wang , Yinxing Miao , Yong Nian , Junyu Zheng , Jie Li , Feng Yan , Gang Li
The balance between CD8+ T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) plays a crucial role in the immune checkpoint inhibition (ICI) therapy in gastric carcinoma (GC). However, related factors leading to the disturbance of TME and resistance to ICI therapy remain unknown. In this study, we applied N6-methyladenosine (m6A) small RNA Epitranscriptomic Microarray and screened out 3'tRF-AlaAGC based on its highest differential expression level and lowest inter-group variance. N6-methyladenosine modification significantly enhanced the stability of 3'tRF-AlaAGC, which strengthened glycolysis and lactic acid (LA) production in GC cells by binding to PTBP1 (Polypyrimidine Tract Binding Protein 1). In the peritoneal GC implantation model established in huPBMC-NCG mice, 3'tRF-AlaAGC significantly increased the proportion of PD1+ Treg cells. Furthermore, in high-LA environments driven by glucose consumption of GC cells, Treg cells actively uptake LA through MCT1, facilitating NFAT1 translocation into the nucleus and enhancing PD1 expression, whereas PD1 expression by effector T cell is diminished. Meanwhile, T cell suppression assays were performed under low-LA or high-LA conditions, and the proliferation of CD8+ T cells was dampened by adding Sintilimab in a high-LA but not in a low-LA environment, suggesting the preferential activation of PD1+ Treg cell. These findings deciphered the complexities of the immune microenvironment in GC, providing prospects for identifying robust biomarkers that could improve the evaluation of therapeutic effectiveness and prognosis in immune therapy for GC.
{"title":"N6-methyladenosine modification of 3'tRF-AlaAGC impairs PD-1 blockade efficacy by promoting lactic acid accumulation in the tumor microenvironment of gastric carcinoma","authors":"Weiguo Xu , Bin Zhou , Ping Wang , Yuyan Ma , Yu Jiang , Dongping Mo , Jun Wu , Jingjing Ma , Xiao Wang , Yinxing Miao , Yong Nian , Junyu Zheng , Jie Li , Feng Yan , Gang Li","doi":"10.1016/j.drup.2024.101197","DOIUrl":"10.1016/j.drup.2024.101197","url":null,"abstract":"<div><div>The balance between CD8<sup>+</sup> T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) plays a crucial role in the immune checkpoint inhibition (ICI) therapy in gastric carcinoma (GC). However, related factors leading to the disturbance of TME and resistance to ICI therapy remain unknown. In this study, we applied N6-methyladenosine (m6A) small RNA Epitranscriptomic Microarray and screened out 3'tRF-AlaAGC based on its highest differential expression level and lowest inter-group variance. N6-methyladenosine modification significantly enhanced the stability of 3'tRF-AlaAGC, which strengthened glycolysis and lactic acid (LA) production in GC cells by binding to <em>PTBP1</em> (Polypyrimidine Tract Binding Protein 1). In the peritoneal GC implantation model established in huPBMC-NCG mice, 3'tRF-AlaAGC significantly increased the proportion of PD1<sup>+</sup> Treg cells. Furthermore, in high-LA environments driven by glucose consumption of GC cells, Treg cells actively uptake LA through <em>MCT1</em>, facilitating <em>NFAT1</em> translocation into the nucleus and enhancing PD1 expression, whereas PD1 expression by effector T cell is diminished. Meanwhile, T cell suppression assays were performed under low-LA or high-LA conditions, and the proliferation of CD8<sup>+</sup> T cells was dampened by adding Sintilimab in a high-LA but not in a low-LA environment, suggesting the preferential activation of PD1<sup>+</sup> Treg cell. These findings deciphered the complexities of the immune microenvironment in GC, providing prospects for identifying robust biomarkers that could improve the evaluation of therapeutic effectiveness and prognosis in immune therapy for GC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101197"},"PeriodicalIF":15.8,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928724","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 : 2024-12-26DOI: 10.1016/j.drup.2024.101195
Xiangyu Ma , Jiamin Xu , Yanan Wang , Joshua S. Fleishman , Hao Bing , Boran Yu , Yanming Li , Letao Bo , Shaolong Zhang , Zhe-Sheng Chen , Libo Zhao
Leukemia is a type of blood cancer characterized by the uncontrolled growth of abnormal cells in the bone marrow, which replace normal blood cells and disrupt normal blood cell function. Timely and personalized interventions are crucial for disease management and improving survival rates. However, many patients experience relapse following conventional chemotherapy, and increasing treatment intensity often fails to improve outcomes due to mutated gene-induced drug resistance in leukemia cells. This article analyzes the association of gene mutations and drug resistance in leukemia. It explores genetic abnormalities in leukemia, highlighting recently identified mutations affecting signaling pathways, cell apoptosis, epigenetic regulation, histone modification, and splicing mechanisms. Additionally, the article discusses therapeutic strategies such as molecular targeting of gene mutations, alternative pathway targeting, and immunotherapy in leukemia. These approaches aim to combat specific drug-resistant mutations, providing potential avenues to mitigate leukemia relapse. Future research with these strategies holds promise for advancing leukemia treatment and addressing the challenges of drug-resistant mutations to improve patient outcomes.
{"title":"Research progress on gene mutations and drug resistance in leukemia","authors":"Xiangyu Ma , Jiamin Xu , Yanan Wang , Joshua S. Fleishman , Hao Bing , Boran Yu , Yanming Li , Letao Bo , Shaolong Zhang , Zhe-Sheng Chen , Libo Zhao","doi":"10.1016/j.drup.2024.101195","DOIUrl":"10.1016/j.drup.2024.101195","url":null,"abstract":"<div><div>Leukemia is a type of blood cancer characterized by the uncontrolled growth of abnormal cells in the bone marrow, which replace normal blood cells and disrupt normal blood cell function. Timely and personalized interventions are crucial for disease management and improving survival rates. However, many patients experience relapse following conventional chemotherapy, and increasing treatment intensity often fails to improve outcomes due to mutated gene-induced drug resistance in leukemia cells. This article analyzes the association of gene mutations and drug resistance in leukemia. It explores genetic abnormalities in leukemia, highlighting recently identified mutations affecting signaling pathways, cell apoptosis, epigenetic regulation, histone modification, and splicing mechanisms. Additionally, the article discusses therapeutic strategies such as molecular targeting of gene mutations, alternative pathway targeting, and immunotherapy in leukemia. These approaches aim to combat specific drug-resistant mutations, providing potential avenues to mitigate leukemia relapse. Future research with these strategies holds promise for advancing leukemia treatment and addressing the challenges of drug-resistant mutations to improve patient outcomes.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101195"},"PeriodicalIF":15.8,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911107","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 : 2024-12-25DOI: 10.1016/j.drup.2024.101194
Huiqiong Jia , Qingchao Tong , Le Wang , Yuye Wu , Xinyang Li , Shuangshuang Li , Yingying Kong , Yingying Zhang , João Pedro Rueda Furlan , Nwai Oo Khine , Patrick Butaye , Jun Zhang , Qing Yang , Zhi Ruan
To characterize the genomic features of a community-acquired Acinetobacter baumannii strain, co-carrying tet(X6) and blaOXA-58 genes, but was susceptible to tigecycline and carbapenems. The tet(X6) and blaOXA-58 genes were found on a 149,518 bp non-conjugative plasmid. The blaOXA-58 gene was silent, due to the presence of an intact ISAba3-like element upstream, which rendered the strain susceptible to carbapenems.
{"title":"Silent circulation of plasmid-borne tet(X6) and blaOXA-58 genes in a community-acquired Acinetobacter baumannii strain","authors":"Huiqiong Jia , Qingchao Tong , Le Wang , Yuye Wu , Xinyang Li , Shuangshuang Li , Yingying Kong , Yingying Zhang , João Pedro Rueda Furlan , Nwai Oo Khine , Patrick Butaye , Jun Zhang , Qing Yang , Zhi Ruan","doi":"10.1016/j.drup.2024.101194","DOIUrl":"10.1016/j.drup.2024.101194","url":null,"abstract":"<div><div>To characterize the genomic features of a community-acquired <em>Acinetobacter baumannii</em> strain, co-carrying <em>tet</em>(X6) and <em>bla</em><sub>OXA-58</sub> genes, but was susceptible to tigecycline and carbapenems. The <em>tet</em>(X6) and <em>bla</em><sub>OXA-58</sub> genes were found on a 149,518 bp non-conjugative plasmid. The <em>bla</em><sub>OXA-58</sub> gene was silent, due to the presence of an intact IS<em>Aba3</em>-like element upstream, which rendered the strain susceptible to carbapenems.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101194"},"PeriodicalIF":15.8,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142889253","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 : 2024-12-24DOI: 10.1016/j.drup.2024.101196
Ke Wu , Xiao-xiao Ge , Xiao-fan Duan , Jie-qing Li , Kun Wang , Qiao-Hong Chen , Zhi-min Huang , Wei-yan Zhang , Yong Wu , Qun Li
PP2C serine-threonine phosphatase Wip1 plays an important role in normal tissue homeostasis, stress signaling and pathogenesis of various human diseases. It is an attractive drug target for cancer treatment and inhibition of its expression or activity constitute a novel therapeutic intervention strategy to prevent the development of various cancers. However, previous strategies for Wip1 suppression may be ineffective in cancers lacking p53. Here, we have characterized the activity of a novel Wip1 phosphatase activator, QGC-8–52, in preclinical models of breast malignancies. QGC-8–52 significantly sensitizes the cancer cell lines with p53 deletion to chemotherapeutic agents. This effect was mediated by the Wip1-FOXO3a interaction and subsequent dephosphorylation of Thr487 that resulted, in response to anticancer treatment, in enhancing the transcription activity of FOXO3a on the proapoptotic TRAIL gene. The sensitizing effect of Wip1 activation on chemotherapeutic drugs only targeted cancer cells lacking p53. The activation of Wip1 in normal cells provided protection from anticancer drug-induced apoptosis by reducing the strength of upstream signaling to p53. Therefore, during the treatment of anticancer drugs, the activated Wip1 phosphatase boosts the apoptosis of p53-negative tumors and protects normal tissues. Our findings may represent an effective and safe therapeutic strategy for cancers with p53 deletion.
{"title":"Wip1 phosphatase activator QGC-8–52 specifically sensitizes p53-negative cancer cells to chemotherapy while protecting normal cells","authors":"Ke Wu , Xiao-xiao Ge , Xiao-fan Duan , Jie-qing Li , Kun Wang , Qiao-Hong Chen , Zhi-min Huang , Wei-yan Zhang , Yong Wu , Qun Li","doi":"10.1016/j.drup.2024.101196","DOIUrl":"10.1016/j.drup.2024.101196","url":null,"abstract":"<div><div>PP2C serine-threonine phosphatase Wip1 plays an important role in normal tissue homeostasis, stress signaling and pathogenesis of various human diseases. It is an attractive drug target for cancer treatment and inhibition of its expression or activity constitute a novel therapeutic intervention strategy to prevent the development of various cancers. However, previous strategies for Wip1 suppression may be ineffective in cancers lacking p53. Here, we have characterized the activity of a novel Wip1 phosphatase activator, QGC-8–52, in preclinical models of breast malignancies. QGC-8–52 significantly sensitizes the cancer cell lines with p53 deletion to chemotherapeutic agents. This effect was mediated by the Wip1-FOXO3a interaction and subsequent dephosphorylation of Thr487 that resulted, in response to anticancer treatment, in enhancing the transcription activity of FOXO3a on the proapoptotic <em>TRAIL</em> gene. The sensitizing effect of Wip1 activation on chemotherapeutic drugs only targeted cancer cells lacking p53. The activation of Wip1 in normal cells provided protection from anticancer drug-induced apoptosis by reducing the strength of upstream signaling to p53. Therefore, during the treatment of anticancer drugs, the activated Wip1 phosphatase boosts the apoptosis of p53-negative tumors and protects normal tissues. Our findings may represent an effective and safe therapeutic strategy for cancers with p53 deletion.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101196"},"PeriodicalIF":15.8,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142958365","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}
The unstable antimicrobial activity of antimicrobial peptides (AMPs) under physiological conditions (especially the degradation instigated proteases) seems to be a persistent impediment for their successful implementation in clinical trials. Consequently, our objective was to devise AMP engineering frameworks that could sustain robust antibacterial efficacy within physiological environments.
Methods
In this work, we harvested AMPs with stable antimicrobial activity under the physiological barriers through the combination of idealized amphiphiles and trypsin inhibitors.
Results
We screened and identified the lead peptides IK3-A and IK3-S, which showed potent activity against Gram-negative bacteria, including multidrug-resistant (MDR) bacteria, and exhibited promising biocompatibility with mammalian cells. Remarkably, IK3-A and IK3-S maintained sustained antibacterial potency under physiological salts, serum, and protease conditions. Furthermore, both IK3-A and IK3-S kill Gram-negative bacteria by attacking the bacterial cell membrane and inducing oxidative damage (at high concentrations). Crucially, IK3-A and IK3-S have optimal safety and efficacy in mice.
Conclusions
This is the first work to compare the effects of different trypsin inhibitors on the resistance of AMPs to protease hydrolysis on the same sequence platform. In conclusion, these findings provide guidance for the molecular design of AMPs with stable antibacterial activity under physiological conditions and facilitates the process of clinical translation of AMPs as antimicrobial biomaterials against MDR bacteria. Moreover, this may stimulate a more general interest in protease inhibitors as molecular scaffolds in the creation of highly stable peptide-based biomaterials.
{"title":"Association of idealized amphiphiles and protease inhibitors: Conferring antimicrobial peptides with stable antibacterial activity under physiological conditions to combat multidrug-resistant bacteria","authors":"Yongjie Zhu , Bowen Li , Wanying Xu, Yuanmengxue Wang, Guoyu Li, Chongpeng Bi, Anshan Shan, Changxuan Shao","doi":"10.1016/j.drup.2024.101183","DOIUrl":"10.1016/j.drup.2024.101183","url":null,"abstract":"<div><h3>Aims</h3><div>The unstable antimicrobial activity of antimicrobial peptides (AMPs) under physiological conditions (especially the degradation instigated proteases) seems to be a persistent impediment for their successful implementation in clinical trials. Consequently, our objective was to devise AMP engineering frameworks that could sustain robust antibacterial efficacy within physiological environments.</div></div><div><h3>Methods</h3><div>In this work, we harvested AMPs with stable antimicrobial activity under the physiological barriers through the combination of idealized amphiphiles and trypsin inhibitors.</div></div><div><h3>Results</h3><div>We screened and identified the lead peptides IK3-A and IK3-S, which showed potent activity against Gram-negative bacteria, including multidrug-resistant (MDR) bacteria, and exhibited promising biocompatibility with mammalian cells. Remarkably, IK3-A and IK3-S maintained sustained antibacterial potency under physiological salts, serum, and protease conditions. Furthermore, both IK3-A and IK3-S kill Gram-negative bacteria by attacking the bacterial cell membrane and inducing oxidative damage (at high concentrations). Crucially, IK3-A and IK3-S have optimal safety and efficacy in mice.</div></div><div><h3>Conclusions</h3><div>This is the first work to compare the effects of different trypsin inhibitors on the resistance of AMPs to protease hydrolysis on the same sequence platform. In conclusion, these findings provide guidance for the molecular design of AMPs with stable antibacterial activity under physiological conditions and facilitates the process of clinical translation of AMPs as antimicrobial biomaterials against MDR bacteria. Moreover, this may stimulate a more general interest in protease inhibitors as molecular scaffolds in the creation of highly stable peptide-based biomaterials.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101183"},"PeriodicalIF":15.8,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142820132","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 : 2024-11-26DOI: 10.1016/j.drup.2024.101177
Philippe Icard , Mathilde Prieto , Antoine Coquerel , Ludovic Fournel , Joseph Gligorov , Johanna Noel , Adrien Mouren , Anthony Dohan , Marco Alifano , Luca Simula
Immunotherapy, either alone or in combination with chemotherapy, has demonstrated limited efficacy in a variety of solid cancers. Several factors contribute to explaining primary or secondary resistance. Among them, cancer cells, whose metabolism frequently relies on aerobic glycolysis, promote exhaustion of cytotoxic immune cells by diverting the glucose in the tumor microenvironment (TME) to their own profit, while secreting lactic acid that sustains the oxidative metabolism of immunosuppressive cells. Here, we propose to combine current treatment based on the use of immune checkpoint inhibitors (ICIs) with high doses of sodium citrate (SCT) because citrate inhibits cancer cell metabolism (by targeting both glycolysis and oxidative metabolism) and may active anti-tumor immune response. Indeed, as showed in preclinical studies, SCT reduces cancer cell growth, promoting cell death and chemotherapy effectiveness. Furthermore, since the plasma membrane citrate carrier pmCIC is mainly expressed in cancer cells and low or not expressed in immune and non-transformed cells, we argue that the inhibition of cancer cell metabolism by SCT may increase glucose availability in the TME, thus promoting functionality of anti-tumor immune cells. Concomitantly, the decrease in the amount of lactic acid in the TME may reduce the functionality of immunosuppressive cells. Preclinical studies have shown that SCT can enhance the anti-tumor immune response through an enhancement of T cell infiltration and activation, and a repolarization of macrophages towards a TAM1-like phenotype. Therefore, this simple and cheap strategy may have a major impact to increase the efficacy of current immunotherapies in human solid tumors and we encourage testing it in clinical trials.
{"title":"Why and how citrate may sensitize malignant tumors to immunotherapy","authors":"Philippe Icard , Mathilde Prieto , Antoine Coquerel , Ludovic Fournel , Joseph Gligorov , Johanna Noel , Adrien Mouren , Anthony Dohan , Marco Alifano , Luca Simula","doi":"10.1016/j.drup.2024.101177","DOIUrl":"10.1016/j.drup.2024.101177","url":null,"abstract":"<div><div>Immunotherapy, either alone or in combination with chemotherapy, has demonstrated limited efficacy in a variety of solid cancers. Several factors contribute to explaining primary or secondary resistance. Among them, cancer cells, whose metabolism frequently relies on aerobic glycolysis, promote exhaustion of cytotoxic immune cells by diverting the glucose in the tumor microenvironment (TME) to their own profit, while secreting lactic acid that sustains the oxidative metabolism of immunosuppressive cells. Here, we propose to combine current treatment based on the use of immune checkpoint inhibitors (ICIs) with high doses of sodium citrate (SCT) because citrate inhibits cancer cell metabolism (by targeting both glycolysis and oxidative metabolism) and may active anti-tumor immune response. Indeed, as showed in preclinical studies, SCT reduces cancer cell growth, promoting cell death and chemotherapy effectiveness. Furthermore, since the plasma membrane citrate carrier pmCIC is mainly expressed in cancer cells and low or not expressed in immune and non-transformed cells, we argue that the inhibition of cancer cell metabolism by SCT may increase glucose availability in the TME, thus promoting functionality of anti-tumor immune cells. Concomitantly, the decrease in the amount of lactic acid in the TME may reduce the functionality of immunosuppressive cells. Preclinical studies have shown that SCT can enhance the anti-tumor immune response through an enhancement of T cell infiltration and activation, and a repolarization of macrophages towards a TAM1-like phenotype. Therefore, this simple and cheap strategy may have a major impact to increase the efficacy of current immunotherapies in human solid tumors and we encourage testing it in clinical trials.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"78 ","pages":"Article 101177"},"PeriodicalIF":15.8,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142721172","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 : 2024-11-23DOI: 10.1016/j.drup.2024.101175
Li Yang , Aitian Li , Weina Yu , Huishang Wang , Lei Zhang , Dan Wang , Ying Wang , Ru Zhang , Qingyang Lei , Zhangnan Liu , Shanshan Zhen , Haiming Qin , Yaqing Liu , Yang Yang , Xian-Lu Song , Yi Zhang
Aims
Immune checkpoint blockade therapy is not effective in most patients with non-small cell lung cancer (NSCLC) due to the immunosuppressive tumor microenvironment. Macrophages are key components of tumor-infiltrating immune cells and play a critical role in immunosuppression, which can be mediated by cell-intrinsic metabolism. This study aimed to evaluate whether macrophages regulate NSCLC progression through metabolic crosstalk with cancer cells and affect immunotherapy efficacy.
Methods
The macrophage landscape of NSCLC tissues were analyzed by single-cell sequencing and verified through flow cytometry and immunofluorescence. Multiplex assay, single-cell sequencing data, ELISA, immunofluorescence, and RNA-seq et al. were used to investigate and verify the mechanism of macrophage-mediated metabolic regulation on immunosuppression. The tumor-bearing model was established in C57BL/6 J mice to explore in vivo efficacy.
Results
We found that tumor tissue-derived macrophages exhibited an anti-inflammatory phenotype and had a prognostic value for NSCLC. NSCLC cell-secreted CXCL8 recruited macrophages from peritumor tissues to tumor sites and promoted programmed death-ligand 1 (PD-L1) expression by activating purine metabolism with increasing xanthine dehydrogenase and uric acid production. Moreover, purine metabolism-mediated macrophage immunosuppression was dependent on NLRP3/caspase-1/IL-1β signaling. Blockade of purine metabolism signaling enhanced anti-tumor immunity and the efficacy of anti-PD-L1 therapy.
Conclusions
Collectively, our findings reveal a key role of purine metabolism in macrophage immunosuppression and suggest that blockade of purine metabolism combined with immune checkpoint blockade could provide synergistic effects in NSCLC treatment.
{"title":"Blockade of purine metabolism reverses macrophage immunosuppression and enhances anti-tumor immunity in non-small cell lung cancer","authors":"Li Yang , Aitian Li , Weina Yu , Huishang Wang , Lei Zhang , Dan Wang , Ying Wang , Ru Zhang , Qingyang Lei , Zhangnan Liu , Shanshan Zhen , Haiming Qin , Yaqing Liu , Yang Yang , Xian-Lu Song , Yi Zhang","doi":"10.1016/j.drup.2024.101175","DOIUrl":"10.1016/j.drup.2024.101175","url":null,"abstract":"<div><h3>Aims</h3><div>Immune checkpoint blockade therapy is not effective in most patients with non-small cell lung cancer (NSCLC) due to the immunosuppressive tumor microenvironment. Macrophages are key components of tumor-infiltrating immune cells and play a critical role in immunosuppression, which can be mediated by cell-intrinsic metabolism. This study aimed to evaluate whether macrophages regulate NSCLC progression through metabolic crosstalk with cancer cells and affect immunotherapy efficacy.</div></div><div><h3>Methods</h3><div>The macrophage landscape of NSCLC tissues were analyzed by single-cell sequencing and verified through flow cytometry and immunofluorescence. Multiplex assay, single-cell sequencing data, ELISA, immunofluorescence, and RNA-seq et al. were used to investigate and verify the mechanism of macrophage-mediated metabolic regulation on immunosuppression. The tumor-bearing model was established in C57BL/6 J mice to explore in vivo efficacy.</div></div><div><h3>Results</h3><div>We found that tumor tissue-derived macrophages exhibited an anti-inflammatory phenotype and had a prognostic value for NSCLC. NSCLC cell-secreted CXCL8 recruited macrophages from peritumor tissues to tumor sites and promoted programmed death-ligand 1 (PD-L1) expression by activating purine metabolism with increasing xanthine dehydrogenase and uric acid production. Moreover, purine metabolism-mediated macrophage immunosuppression was dependent on NLRP3/caspase-1/IL-1β signaling. Blockade of purine metabolism signaling enhanced anti-tumor immunity and the efficacy of anti-PD-L1 therapy.</div></div><div><h3>Conclusions</h3><div>Collectively, our findings reveal a key role of purine metabolism in macrophage immunosuppression and suggest that blockade of purine metabolism combined with immune checkpoint blockade could provide synergistic effects in NSCLC treatment.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"78 ","pages":"Article 101175"},"PeriodicalIF":15.8,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142721164","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 : 2024-11-21DOI: 10.1016/j.drup.2024.101173
Chenggui Miao , Yurong Huang , Cheng Zhang , Xiao Wang , Bing Wang , Xinyue Zhou , Yingqiu Song , Peng Wu , Zhe-Sheng Chen , Yibin Feng
Resistance to antitumor drugs, antimicrobial drugs, and antiviral drugs severely limits treatment effectiveness and cure rate of diseases. Protein post-translational modifications (PTMs) represented by glycosylation, ubiquitination, SUMOylation, acetylation, phosphorylation, palmitoylation, and lactylation are closely related to drug resistance. PTMs are typically achieved by adding sugar chains (glycosylation), small proteins (ubiquitination), lipids (palmitoylation), or functional groups (lactylation) to amino acid residues. These covalent additions are usually the results of signaling cascades and could be reversible, with the triggering mechanisms depending on the type of modifications. PTMs are involved in antitumor drug resistance, not only as inducers of drug resistance but also as targets for reversing drug resistance. Bacteria exhibit multiple PTMs-mediated antimicrobial drug resistance. PTMs allow viral proteins and host cell proteins to form complex interaction networks, inducing complex antiviral drug resistance. This review summarizes the important roles of PTMs in drug resistance, providing new ideas for exploring drug resistance mechanisms, developing new drug targets, and guiding treatment plans.
{"title":"Post-translational modifications in drug resistance","authors":"Chenggui Miao , Yurong Huang , Cheng Zhang , Xiao Wang , Bing Wang , Xinyue Zhou , Yingqiu Song , Peng Wu , Zhe-Sheng Chen , Yibin Feng","doi":"10.1016/j.drup.2024.101173","DOIUrl":"10.1016/j.drup.2024.101173","url":null,"abstract":"<div><div>Resistance to antitumor drugs, antimicrobial drugs, and antiviral drugs severely limits treatment effectiveness and cure rate of diseases. Protein post-translational modifications (PTMs) represented by glycosylation, ubiquitination, SUMOylation, acetylation, phosphorylation, palmitoylation, and lactylation are closely related to drug resistance. PTMs are typically achieved by adding sugar chains (glycosylation), small proteins (ubiquitination), lipids (palmitoylation), or functional groups (lactylation) to amino acid residues. These covalent additions are usually the results of signaling cascades and could be reversible, with the triggering mechanisms depending on the type of modifications. PTMs are involved in antitumor drug resistance, not only as inducers of drug resistance but also as targets for reversing drug resistance. Bacteria exhibit multiple PTMs-mediated antimicrobial drug resistance. PTMs allow viral proteins and host cell proteins to form complex interaction networks, inducing complex antiviral drug resistance. This review summarizes the important roles of PTMs in drug resistance, providing new ideas for exploring drug resistance mechanisms, developing new drug targets, and guiding treatment plans.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"78 ","pages":"Article 101173"},"PeriodicalIF":15.8,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142721173","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}
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