Pub Date : 2023-10-11DOI: 10.1038/s41568-023-00615-0
Thomas Gebhardt, Simone L. Park, Ian A. Parish
T cells can acquire a broad spectrum of differentiation states following activation. At the extreme ends of this continuum are short-lived cells equipped with effector machinery and more quiescent, long-lived cells with heightened proliferative potential and stem cell-like developmental plasticity. The latter encompass stem-like exhausted T cells and memory T cells, both of which have recently emerged as key determinants of cancer immunity and response to immunotherapy. Here, we discuss key similarities and differences in the regulation and function of stem-like exhausted CD8+ T cells and memory CD8+ T cells, and consider their context-specific contributions to protective immunity in diverse outcomes of cancer, including tumour escape, long-term control and eradication. Finally, we emphasize how recent advances in the understanding of the molecular regulation of stem-like exhausted T cells and memory T cells are being explored for clinical benefit in cancer immunotherapies such as checkpoint inhibition, adoptive cell therapy and vaccination. T cells can acquire a broad spectrum of differentiation states following activation; certain subtypes of T cells have emerged as key determinants of cancer immunity and response to immunotherapies. Here, Gebhardt, Park and Parish discuss the phenotypic and functional variation of stem-like exhausted CD8+ T cells and memory CD8+ T cells, and how it contributes to their roles in immune escape and cancer outcome.
{"title":"Stem-like exhausted and memory CD8+ T cells in cancer","authors":"Thomas Gebhardt, Simone L. Park, Ian A. Parish","doi":"10.1038/s41568-023-00615-0","DOIUrl":"10.1038/s41568-023-00615-0","url":null,"abstract":"T cells can acquire a broad spectrum of differentiation states following activation. At the extreme ends of this continuum are short-lived cells equipped with effector machinery and more quiescent, long-lived cells with heightened proliferative potential and stem cell-like developmental plasticity. The latter encompass stem-like exhausted T cells and memory T cells, both of which have recently emerged as key determinants of cancer immunity and response to immunotherapy. Here, we discuss key similarities and differences in the regulation and function of stem-like exhausted CD8+ T cells and memory CD8+ T cells, and consider their context-specific contributions to protective immunity in diverse outcomes of cancer, including tumour escape, long-term control and eradication. Finally, we emphasize how recent advances in the understanding of the molecular regulation of stem-like exhausted T cells and memory T cells are being explored for clinical benefit in cancer immunotherapies such as checkpoint inhibition, adoptive cell therapy and vaccination. T cells can acquire a broad spectrum of differentiation states following activation; certain subtypes of T cells have emerged as key determinants of cancer immunity and response to immunotherapies. Here, Gebhardt, Park and Parish discuss the phenotypic and functional variation of stem-like exhausted CD8+ T cells and memory CD8+ T cells, and how it contributes to their roles in immune escape and cancer outcome.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 11","pages":"780-798"},"PeriodicalIF":78.5,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41206535","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 : 2023-10-09DOI: 10.1038/s41568-023-00611-4
Alexandra M. Pinzaru, Sohail F. Tavazoie
Transfer RNAs (tRNAs) have been historically viewed as non-dynamic adaptors that decode the genetic code into proteins. Recent work has uncovered dynamic regulatory roles for these fascinating molecules. Advances in tRNA detection methods have revealed that specific tRNAs can become modulated upon DNA copy number and chromatin alterations and can also be perturbed by oncogenic signalling and transcriptional regulators in cancer cells or the tumour microenvironment. Such alterations in the levels of specific tRNAs have been shown to causally impact cancer progression, including metastasis. Moreover, sequencing methods have identified tRNA-derived small RNAs that influence various aspects of cancer progression, such as cell proliferation and invasion, and could serve as diagnostic and prognostic biomarkers or putative therapeutic targets in various cancers. Finally, there is accumulating evidence, including from genetic models, that specific tRNA synthetases — the enzymes responsible for charging tRNAs with amino acids — can either promote or suppress tumour formation. In this Review, we provide an overview of how deregulation of tRNAs influences cancer formation and progression. Transfer RNAs have long been known as static adaptors that translate the genetic code but are now emerging as dynamic regulators in health and disease, including cancer. This Review discusses how the deregulation of the tRNA pool, tRNA-derived small RNAs and tRNA synthetases impacts tumour initiation and progression.
{"title":"Transfer RNAs as dynamic and critical regulators of cancer progression","authors":"Alexandra M. Pinzaru, Sohail F. Tavazoie","doi":"10.1038/s41568-023-00611-4","DOIUrl":"10.1038/s41568-023-00611-4","url":null,"abstract":"Transfer RNAs (tRNAs) have been historically viewed as non-dynamic adaptors that decode the genetic code into proteins. Recent work has uncovered dynamic regulatory roles for these fascinating molecules. Advances in tRNA detection methods have revealed that specific tRNAs can become modulated upon DNA copy number and chromatin alterations and can also be perturbed by oncogenic signalling and transcriptional regulators in cancer cells or the tumour microenvironment. Such alterations in the levels of specific tRNAs have been shown to causally impact cancer progression, including metastasis. Moreover, sequencing methods have identified tRNA-derived small RNAs that influence various aspects of cancer progression, such as cell proliferation and invasion, and could serve as diagnostic and prognostic biomarkers or putative therapeutic targets in various cancers. Finally, there is accumulating evidence, including from genetic models, that specific tRNA synthetases — the enzymes responsible for charging tRNAs with amino acids — can either promote or suppress tumour formation. In this Review, we provide an overview of how deregulation of tRNAs influences cancer formation and progression. Transfer RNAs have long been known as static adaptors that translate the genetic code but are now emerging as dynamic regulators in health and disease, including cancer. This Review discusses how the deregulation of the tRNA pool, tRNA-derived small RNAs and tRNA synthetases impacts tumour initiation and progression.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 11","pages":"746-761"},"PeriodicalIF":78.5,"publicationDate":"2023-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41183133","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 : 2023-09-28DOI: 10.1038/s41568-023-00627-w
Nicolas Mathey-Andrews
In this Tool of the Trade article, Nicolas Mathey-Andrews describes the generation and use of a prime editor mouse that enables in vivo modelling of the multitude of cancer alleles found in human tumours.
{"title":"Prime editing GEMMs to model cancer mutations","authors":"Nicolas Mathey-Andrews","doi":"10.1038/s41568-023-00627-w","DOIUrl":"10.1038/s41568-023-00627-w","url":null,"abstract":"In this Tool of the Trade article, Nicolas Mathey-Andrews describes the generation and use of a prime editor mouse that enables in vivo modelling of the multitude of cancer alleles found in human tumours.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"24 1","pages":"2-2"},"PeriodicalIF":78.5,"publicationDate":"2023-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41105026","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 : 2023-09-27DOI: 10.1038/s41568-023-00631-0
Gabrielle Brewer
Karttunen et al. identify the contribution of transposable elements to gene regulatory function in colorectal and liver cancer cell lines.
Karttunen 等人确定了转座元件对结直肠癌和肝癌细胞系基因调控功能的贡献。
{"title":"Enhanced transposable elements","authors":"Gabrielle Brewer","doi":"10.1038/s41568-023-00631-0","DOIUrl":"10.1038/s41568-023-00631-0","url":null,"abstract":"Karttunen et al. identify the contribution of transposable elements to gene regulatory function in colorectal and liver cancer cell lines.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 11","pages":"729-729"},"PeriodicalIF":78.5,"publicationDate":"2023-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41105025","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 : 2023-09-27DOI: 10.1038/s41568-023-00626-x
Gabriela Sarti Kinker, Tiago da Silva Medina
In this Journal Club, Kinker & Medina discuss a study showing the role of tumour-associated tertiary lymphoid structures in improving immunotherapy response and overall survival in patients with melanoma.
{"title":"Tertiary lymphoid structures as hubs of antitumour immunity","authors":"Gabriela Sarti Kinker, Tiago da Silva Medina","doi":"10.1038/s41568-023-00626-x","DOIUrl":"10.1038/s41568-023-00626-x","url":null,"abstract":"In this Journal Club, Kinker & Medina discuss a study showing the role of tumour-associated tertiary lymphoid structures in improving immunotherapy response and overall survival in patients with melanoma.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 12","pages":"803-803"},"PeriodicalIF":78.5,"publicationDate":"2023-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41143386","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 : 2023-09-27DOI: 10.1038/s41568-023-00629-8
Daniela Senft
In a recent study, Tagore et al. find that the formation of synapse-like structures that serve to transfer GABA between premalignant melanocytes and keratinocytes promotes melanoma initiation by the BRAFV600E oncogene.
{"title":"Synaptic activity promotes melanoma formation","authors":"Daniela Senft","doi":"10.1038/s41568-023-00629-8","DOIUrl":"10.1038/s41568-023-00629-8","url":null,"abstract":"In a recent study, Tagore et al. find that the formation of synapse-like structures that serve to transfer GABA between premalignant melanocytes and keratinocytes promotes melanoma initiation by the BRAFV600E oncogene.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 11","pages":"728-728"},"PeriodicalIF":78.5,"publicationDate":"2023-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41119902","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 : 2023-09-27DOI: 10.1038/s41568-023-00630-1
Daniela Senft
In a recent study, Sanchez-Aguilera, Masmudi-Martín et al. find that a molecular program explains the cognitive impairment often seen in patients with brain metastasis, challenging the prevailing paradigm of the tumour mass being the sole cause of altered brain function.
{"title":"Computing brain metastasis impact","authors":"Daniela Senft","doi":"10.1038/s41568-023-00630-1","DOIUrl":"10.1038/s41568-023-00630-1","url":null,"abstract":"In a recent study, Sanchez-Aguilera, Masmudi-Martín et al. find that a molecular program explains the cognitive impairment often seen in patients with brain metastasis, challenging the prevailing paradigm of the tumour mass being the sole cause of altered brain function.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 11","pages":"729-729"},"PeriodicalIF":78.5,"publicationDate":"2023-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41153578","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 : 2023-09-25DOI: 10.1038/s41568-023-00625-y
Dezhong Ji
In this Tools of the Trade article, Dezhong Ji describes the development and use of a chimeric antigenic peptide influenza virus (CAP-Flu) system as a cancer vaccine strategy to promote tumour-infiltrating T cell activation in lung metastasis.
在这篇 "贸易工具"（Tools of the Trade）文章中，季德忠介绍了嵌合抗原肽流感病毒（CAP-Flu）系统作为癌症疫苗策略的开发和使用情况，以促进肺转移中肿瘤浸润性 T 细胞的活化。
{"title":"Harnessing the influenza virus to fight cancer","authors":"Dezhong Ji","doi":"10.1038/s41568-023-00625-y","DOIUrl":"10.1038/s41568-023-00625-y","url":null,"abstract":"In this Tools of the Trade article, Dezhong Ji describes the development and use of a chimeric antigenic peptide influenza virus (CAP-Flu) system as a cancer vaccine strategy to promote tumour-infiltrating T cell activation in lung metastasis.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"24 1","pages":"1-1"},"PeriodicalIF":78.5,"publicationDate":"2023-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41146796","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 : 2023-09-18DOI: 10.1038/s41568-023-00622-1
Eric K. Lau
On the basis of personal experiences and in light of current US socio-political realities, Eric Lau advocates for proactive actions against discrimination and emphasizes the need to speak out against oppression, urging research institutions to prioritize diversity, equity and inclusion.
{"title":"Research does not happen in a socio-political vacuum — we should not pretend that it does","authors":"Eric K. Lau","doi":"10.1038/s41568-023-00622-1","DOIUrl":"10.1038/s41568-023-00622-1","url":null,"abstract":"On the basis of personal experiences and in light of current US socio-political realities, Eric Lau advocates for proactive actions against discrimination and emphasizes the need to speak out against oppression, urging research institutions to prioritize diversity, equity and inclusion.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 11","pages":"725-726"},"PeriodicalIF":78.5,"publicationDate":"2023-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10308535","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 : 2023-09-15DOI: 10.1038/s41568-023-00612-3
Andaleeb Sajid, Hadiar Rahman, Suresh V. Ambudkar
Cancer cells frequently display intrinsic or acquired resistance to chemically diverse anticancer drugs, limiting therapeutic success. Among the main mechanisms of this multidrug resistance is the overexpression of ATP-binding cassette (ABC) transporters that mediate drug efflux, and, specifically, ABCB1, ABCG2 and ABCC1 are known to cause cancer chemoresistance. High-resolution structures, biophysical and in silico studies have led to tremendous progress in understanding the mechanism of drug transport by these ABC transporters, and several promising therapies, including irradiation-based immune and thermal therapies, and nanomedicine have been used to overcome ABC transporter-mediated cancer chemoresistance. In this Review, we highlight the progress achieved in the past 5 years on the three transporters, ABCB1, ABCG2 and ABCC1, that are known to be of clinical importance. We address the molecular basis of their broad substrate specificity gleaned from structural information and discuss novel approaches to block the function of ABC transporters. Furthermore, genetic modification of ABC transporters by CRISPR–Cas9 and approaches to re-engineer amino acid sequences to change the direction of transport from efflux to import are briefly discussed. We suggest that current information regarding the structure, mechanism and regulation of ABC transporters should be used in clinical trials to improve the efficiency of chemotherapeutics for patients with cancer. This Review summarizes how the structural details that were revealed by cryo-electron microscopy and X-ray crystallography and insights into molecular basis of polyspecificity and mechanistic studies shaped the understanding of the role of ATP-binding cassette transporter in cancer multidrug resistance, culminating in new therapeutic approaches to sensitize multidrug-resistant cancer cells to conventional and targeted therapies.
{"title":"Advances in the structure, mechanism and targeting of chemoresistance-linked ABC transporters","authors":"Andaleeb Sajid, Hadiar Rahman, Suresh V. Ambudkar","doi":"10.1038/s41568-023-00612-3","DOIUrl":"10.1038/s41568-023-00612-3","url":null,"abstract":"Cancer cells frequently display intrinsic or acquired resistance to chemically diverse anticancer drugs, limiting therapeutic success. Among the main mechanisms of this multidrug resistance is the overexpression of ATP-binding cassette (ABC) transporters that mediate drug efflux, and, specifically, ABCB1, ABCG2 and ABCC1 are known to cause cancer chemoresistance. High-resolution structures, biophysical and in silico studies have led to tremendous progress in understanding the mechanism of drug transport by these ABC transporters, and several promising therapies, including irradiation-based immune and thermal therapies, and nanomedicine have been used to overcome ABC transporter-mediated cancer chemoresistance. In this Review, we highlight the progress achieved in the past 5 years on the three transporters, ABCB1, ABCG2 and ABCC1, that are known to be of clinical importance. We address the molecular basis of their broad substrate specificity gleaned from structural information and discuss novel approaches to block the function of ABC transporters. Furthermore, genetic modification of ABC transporters by CRISPR–Cas9 and approaches to re-engineer amino acid sequences to change the direction of transport from efflux to import are briefly discussed. We suggest that current information regarding the structure, mechanism and regulation of ABC transporters should be used in clinical trials to improve the efficiency of chemotherapeutics for patients with cancer. This Review summarizes how the structural details that were revealed by cryo-electron microscopy and X-ray crystallography and insights into molecular basis of polyspecificity and mechanistic studies shaped the understanding of the role of ATP-binding cassette transporter in cancer multidrug resistance, culminating in new therapeutic approaches to sensitize multidrug-resistant cancer cells to conventional and targeted therapies.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 11","pages":"762-779"},"PeriodicalIF":78.5,"publicationDate":"2023-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10610479","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}
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