Pub Date : 2024-07-01DOI: 10.1158/2159-8290.CD-24-0377
Javier Carmona, Elena Chavarria, Kate Donoghue, Christina von Gertten, Petra Oberrauch, Emma Pailler, Giovanni Scoazec, Ruud Weijer, Judith Balmaña, Irene Brana, Cinzia Brunelli, Suzette Delaloge, Marc Deloger, Pierre Delpy, Ingemar Ernberg, Rebecca C Fitzgerald, Elena Garralda, Martin Lablans, Janne Lëhtio, Carlos Lopez, Maialen Fernández, Rosalba Miceli, Paolo Nuciforo, Raquel Perez-Lopez, Elena Provenzano, Marjanka K Schmidt, Cesar Serrano, Neeltje Steeghs, David Tamborero, Valtteri Wirta, Richard D Baird, Karen Barker, Fabrice Barlesi, Michael Baumann, Jonas Bergh, Filippo de Braud, Karim Fizazi, Stefan Fröhling, Alejandro Piris-Giménez, Kenneth Seamon, Michiel S Van der Heijden, Wilbert Zwart, Josep Tabernero
Cancer Core Europe brings together the expertise, resources, and interests of seven leading cancer institutes committed to leveraging collective innovation and collaboration in precision oncology. Through targeted efforts addressing key medical challenges in cancer and partnerships with multiple stakeholders, the consortium seeks to advance cancer research and enhance equitable patient care.
{"title":"Cancer Core Europe: Leveraging Institutional Synergies to Advance Oncology Research and Care Globally.","authors":"Javier Carmona, Elena Chavarria, Kate Donoghue, Christina von Gertten, Petra Oberrauch, Emma Pailler, Giovanni Scoazec, Ruud Weijer, Judith Balmaña, Irene Brana, Cinzia Brunelli, Suzette Delaloge, Marc Deloger, Pierre Delpy, Ingemar Ernberg, Rebecca C Fitzgerald, Elena Garralda, Martin Lablans, Janne Lëhtio, Carlos Lopez, Maialen Fernández, Rosalba Miceli, Paolo Nuciforo, Raquel Perez-Lopez, Elena Provenzano, Marjanka K Schmidt, Cesar Serrano, Neeltje Steeghs, David Tamborero, Valtteri Wirta, Richard D Baird, Karen Barker, Fabrice Barlesi, Michael Baumann, Jonas Bergh, Filippo de Braud, Karim Fizazi, Stefan Fröhling, Alejandro Piris-Giménez, Kenneth Seamon, Michiel S Van der Heijden, Wilbert Zwart, Josep Tabernero","doi":"10.1158/2159-8290.CD-24-0377","DOIUrl":"10.1158/2159-8290.CD-24-0377","url":null,"abstract":"<p><p>Cancer Core Europe brings together the expertise, resources, and interests of seven leading cancer institutes committed to leveraging collective innovation and collaboration in precision oncology. Through targeted efforts addressing key medical challenges in cancer and partnerships with multiple stakeholders, the consortium seeks to advance cancer research and enhance equitable patient care.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141316747","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}
Bone is the most common site of breast cancer metastasis. Bone metastasis is incurable and is associated with severe morbidity. Utilizing an immunocompetent mouse model of spontaneous breast cancer bone metastasis, we profiled the immune transcriptome of bone metastatic lesions and peripheral bone marrow at distinct metastatic stages, revealing dynamic changes during the metastatic process. We show that cross-talk between granulocytes and T cells is central to shaping an immunosuppressive microenvironment. Specifically, we identified the PD-1 and TIGIT signaling axes and the proinflammatory cytokine IL1β as central players in the interactions between granulocytes and T cells. Targeting these pathways in vivo resulted in attenuated bone metastasis and improved survival, by reactivating antitumor immunity. Analysis of patient samples revealed that TIGIT and IL1β are prominent in human bone metastasis. Our findings suggest that cotargeting immunosuppressive granulocytes and dysfunctional T cells may be a promising novel therapeutic strategy to inhibit bone metastasis. Significance: Temporal transcriptome profiling of the immune microenvironment in breast cancer bone metastasis revealed key communication pathways between dysfunctional T cells and myeloid derived suppressor cells. Cotargeting of TIGIT and IL1β inhibited bone metastasis and improved survival. Validation in patient data implicated these targets as a novel promising approach to treat human bone metastasis.
骨是乳腺癌最常见的转移部位。骨转移是无法治愈的,而且与严重的发病率有关。我们利用免疫功能正常的自发性乳腺癌骨转移小鼠模型,分析了骨转移病灶和外周骨髓在不同转移阶段的免疫转录组,揭示了转移过程中的动态变化。我们发现,粒细胞和 T 细胞之间的串扰是形成免疫抑制微环境的核心。具体来说,我们发现 PD-1 和 TIGIT 信号轴以及促炎细胞因子 IL1b 是粒细胞和 T 细胞之间相互作用的核心角色。在体内靶向这些通路可重新激活抗肿瘤免疫,从而减少骨转移并提高生存率。对患者样本的分析表明,TIGIT和IL1b在人类骨转移中表现突出。我们的研究结果表明,联合靶向免疫抑制性粒细胞和功能失调的T细胞可能是一种很有前景的抑制骨转移的新型治疗策略。
{"title":"Combining TIGIT Blockade with MDSC Inhibition Hinders Breast Cancer Bone Metastasis by Activating Antitumor Immunity.","authors":"Lea Monteran, Nour Ershaid, Ye'ela Scharff, Yazeed Zoabi, Tamer Sanalla, Yunfeng Ding, Anna Pavlovsky, Yael Zait, Marva Langer, Tal Caller, Anat Eldar-Boock, Camila Avivi, Amir Sonnenblick, Ronit Satchi-Fainaro, Iris Barshack, Noam Shomron, Xiang H-F Zhang, Neta Erez","doi":"10.1158/2159-8290.CD-23-0762","DOIUrl":"10.1158/2159-8290.CD-23-0762","url":null,"abstract":"<p><p>Bone is the most common site of breast cancer metastasis. Bone metastasis is incurable and is associated with severe morbidity. Utilizing an immunocompetent mouse model of spontaneous breast cancer bone metastasis, we profiled the immune transcriptome of bone metastatic lesions and peripheral bone marrow at distinct metastatic stages, revealing dynamic changes during the metastatic process. We show that cross-talk between granulocytes and T cells is central to shaping an immunosuppressive microenvironment. Specifically, we identified the PD-1 and TIGIT signaling axes and the proinflammatory cytokine IL1β as central players in the interactions between granulocytes and T cells. Targeting these pathways in vivo resulted in attenuated bone metastasis and improved survival, by reactivating antitumor immunity. Analysis of patient samples revealed that TIGIT and IL1β are prominent in human bone metastasis. Our findings suggest that cotargeting immunosuppressive granulocytes and dysfunctional T cells may be a promising novel therapeutic strategy to inhibit bone metastasis. Significance: Temporal transcriptome profiling of the immune microenvironment in breast cancer bone metastasis revealed key communication pathways between dysfunctional T cells and myeloid derived suppressor cells. Cotargeting of TIGIT and IL1β inhibited bone metastasis and improved survival. Validation in patient data implicated these targets as a novel promising approach to treat human bone metastasis.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140012209","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 : 2024-07-01DOI: 10.1158/2159-8290.CD-24-0612
Aayoung Hong, Gatien Moriceau, Lu Sun, Shirley Lomeli, Marco Piva, Robert Damoiseaux, Sheri L Holmen, Norman E Sharpless, Willy Hugo, Roger S Lo
{"title":"Expression of Concern: Exploiting Drug Addiction Mechanisms to Select against MAPKi-Resistant Melanoma.","authors":"Aayoung Hong, Gatien Moriceau, Lu Sun, Shirley Lomeli, Marco Piva, Robert Damoiseaux, Sheri L Holmen, Norman E Sharpless, Willy Hugo, Roger S Lo","doi":"10.1158/2159-8290.CD-24-0612","DOIUrl":"10.1158/2159-8290.CD-24-0612","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466375","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 : 2024-07-01DOI: 10.1158/2159-8290.CD-24-0539
Matthew J Hangauer, Jorge Silvio Gutkind, Fleur M Ferguson
In this issue, Ryan and colleagues describe the preclinical development of a pan-RAF:MEK molecular glue with superior efficacy, brain penetrance, and tolerability in xenograft models of Ras/Raf/MAPK pathway-driven tumors. See related article by Ryan et al., p. 1190 (1).
在本期杂志中,Ryan 及其同事介绍了泛 RAF:MEK 分子胶的临床前开发情况,该分子胶在 Ras/Raf/MAPK 通路驱动的肿瘤异种移植模型中具有卓越的疗效、脑穿透性和耐受性。请参见 Ryan 等人的相关文章,第 1190 页(1)。
{"title":"Pan-RAF:MEK Molecular Glues Take Center Stage.","authors":"Matthew J Hangauer, Jorge Silvio Gutkind, Fleur M Ferguson","doi":"10.1158/2159-8290.CD-24-0539","DOIUrl":"10.1158/2159-8290.CD-24-0539","url":null,"abstract":"<p><p>In this issue, Ryan and colleagues describe the preclinical development of a pan-RAF:MEK molecular glue with superior efficacy, brain penetrance, and tolerability in xenograft models of Ras/Raf/MAPK pathway-driven tumors. See related article by Ryan et al., p. 1190 (1).</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466376","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 : 2024-07-01DOI: 10.1158/2159-8290.CD-24-0538
Pasquale Lombardi, David J Pinato
Transforming gut microbial status from a prognostic trait to a therapeutic target is a key goal to understand and reverse resistance to anticancer immunotherapy. Glitza and colleagues propose selective manipulation of the gut microbiome with SER401 following antibiotic preconditioning and highlight multiple challenges in delivering microbiome manipulation to the clinic. See related article by Glitza et al., p. 1161 (8).
{"title":"Precision Targeting of the Gut Microbiome for Cancer Immunotherapy.","authors":"Pasquale Lombardi, David J Pinato","doi":"10.1158/2159-8290.CD-24-0538","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0538","url":null,"abstract":"<p><p>Transforming gut microbial status from a prognostic trait to a therapeutic target is a key goal to understand and reverse resistance to anticancer immunotherapy. Glitza and colleagues propose selective manipulation of the gut microbiome with SER401 following antibiotic preconditioning and highlight multiple challenges in delivering microbiome manipulation to the clinic. See related article by Glitza et al., p. 1161 (8).</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466377","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 : 2024-07-01DOI: 10.1158/2159-8290.CD-23-0428
Jad I Belle, Devashish Sen, John M Baer, Xiuting Liu, Varintra E Lander, Jiayu Ye, Blake E Sells, Brett L Knolhoff, Ahmad Faiz, Liang-I Kang, Guhan Qian, Ryan C Fields, Li Ding, Hyun Kim, Paolo P Provenzano, Sheila A Stewart, David G DeNardo
Pancreatic ductal adenocarcinoma (PDAC) therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer-associated fibroblasts (CAF). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAF) in mouse and human PDAC. These SenCAFs are a phenotypically distinct subset of myofibroblastic CAFs that localize near tumor ducts and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we used an LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Depletion of senescent stromal cells in genetic and pharmacologic PDAC models relieved immune suppression by macrophages, delayed tumor progression, and increased responsiveness to chemotherapy. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction. Significance: CAF heterogeneity in PDAC remains poorly understood. In this study, we identify a novel subpopulation of senescent CAFs that promotes PDAC progression and immunosuppression. Targeting CAF senescence in combination therapies could increase tumor vulnerability to chemo or immunotherapy. See related article by Ye et al., p. 1302.
{"title":"Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer.","authors":"Jad I Belle, Devashish Sen, John M Baer, Xiuting Liu, Varintra E Lander, Jiayu Ye, Blake E Sells, Brett L Knolhoff, Ahmad Faiz, Liang-I Kang, Guhan Qian, Ryan C Fields, Li Ding, Hyun Kim, Paolo P Provenzano, Sheila A Stewart, David G DeNardo","doi":"10.1158/2159-8290.CD-23-0428","DOIUrl":"10.1158/2159-8290.CD-23-0428","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer-associated fibroblasts (CAF). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAF) in mouse and human PDAC. These SenCAFs are a phenotypically distinct subset of myofibroblastic CAFs that localize near tumor ducts and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we used an LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Depletion of senescent stromal cells in genetic and pharmacologic PDAC models relieved immune suppression by macrophages, delayed tumor progression, and increased responsiveness to chemotherapy. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction. Significance: CAF heterogeneity in PDAC remains poorly understood. In this study, we identify a novel subpopulation of senescent CAFs that promotes PDAC progression and immunosuppression. Targeting CAF senescence in combination therapies could increase tumor vulnerability to chemo or immunotherapy. See related article by Ye et al., p. 1302.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140850841","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 : 2024-07-01DOI: 10.1158/2159-8290.CD-24-0613
Aayoung Hong, Marco Piva, Sixue Liu, Willy Hugo, Shirley H Lomeli, Vincent Zoete, Christopher E Randolph, Zhentao Yang, Yan Wang, Jordan J Lee, Skylar J Lo, Lu Sun, Agustin Vega-Crespo, Alejandro J Garcia, David B Shackelford, Steven M Dubinett, Philip O Scumpia, Stephanie D Byrum, Alan J Tackett, Timothy R Donahue, Olivier Michielin, Sheri L Holmen, Antoni Ribas, Gatien Moriceau, Roger S Lo
{"title":"Expression of Concern: Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Antitumor T-cell Immunity.","authors":"Aayoung Hong, Marco Piva, Sixue Liu, Willy Hugo, Shirley H Lomeli, Vincent Zoete, Christopher E Randolph, Zhentao Yang, Yan Wang, Jordan J Lee, Skylar J Lo, Lu Sun, Agustin Vega-Crespo, Alejandro J Garcia, David B Shackelford, Steven M Dubinett, Philip O Scumpia, Stephanie D Byrum, Alan J Tackett, Timothy R Donahue, Olivier Michielin, Sheri L Holmen, Antoni Ribas, Gatien Moriceau, Roger S Lo","doi":"10.1158/2159-8290.CD-24-0613","DOIUrl":"10.1158/2159-8290.CD-24-0613","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466374","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 : 2024-07-01DOI: 10.1158/2159-8290.CD-23-1266
Kelly D Moynihan, Manu P Kumar, Hussein Sultan, Danielle C Pappas, Terrence Park, S Michael Chin, Paul Bessette, Ruth Y Lan, Henry C Nguyen, Nathan D Mathewson, Irene Ni, Wei Chen, Yonghee Lee, Sindy Liao-Chan, Jessie Chen, Ton N M Schumacher, Robert D Schreiber, Yik A Yeung, Ivana M Djuretic
IL2 signals pleiotropically on diverse cell types, some of which contribute to therapeutic activity against tumors, whereas others drive undesired activity, such as immunosuppression or toxicity. We explored the theory that targeting of IL2 to CD8+ T cells, which are key antitumor effectors, could enhance its therapeutic index. To this aim, we developed AB248, a CD8 cis-targeted IL2 that demonstrates over 500-fold preference for CD8+ T cells over natural killer and regulatory T cells (Tregs), which may contribute to toxicity and immunosuppression, respectively. AB248 recapitulated IL2's effects on CD8+ T cells in vitro and induced selective expansion of CD8+T cells in primates. In mice, an AB248 surrogate demonstrated superior antitumor activity and enhanced tolerability as compared with an untargeted IL2Rβγ agonist. Efficacy was associated with the expansion and phenotypic enhancement of tumor-infiltrating CD8+ T cells, including the emergence of a "better effector" population. These data support the potential utility of AB248 in clinical settings. Significance: The full potential of IL2 therapy remains to be unlocked. We demonstrate that toxicity can be decoupled from antitumor activity in preclinical models by limiting IL2 signaling to CD8+ T cells, supporting the development of CD8+ T cell-selective IL2 for the treatment of cancer. See related article by Kaptein et al. p. 1226.
IL-2对不同类型的细胞产生多重信号,其中一些有助于提高抗肿瘤治疗活性,而另一些则会产生不良活性,如免疫抑制或毒性。我们探索的理论是,将 IL-2 靶向作为关键抗肿瘤效应因子的 CD8+ T 细胞,可以提高 IL-2 的治疗指数。为此,我们开发了CD8顺式靶向IL-2 AB248,它对CD8+ T细胞的偏好超过NK和Treg细胞500倍,而NK和Treg细胞可能分别导致毒性和免疫抑制。AB248 在体外再现了 IL-2 对 CD8+ T 细胞的作用,并在灵长类动物中诱导 CD8+ T 细胞的选择性扩增。在小鼠体内,AB248替代物与非靶向IL-2RBy激动剂相比,表现出更强的抗肿瘤活性和耐受性。疗效与肿瘤浸润性 CD8+ T 细胞的扩增和表型增强有关,包括 "更好效应 "群体的出现。这些数据支持AB248在临床中的潜在用途。
{"title":"IL2 Targeted to CD8+ T Cells Promotes Robust Effector T-cell Responses and Potent Antitumor Immunity.","authors":"Kelly D Moynihan, Manu P Kumar, Hussein Sultan, Danielle C Pappas, Terrence Park, S Michael Chin, Paul Bessette, Ruth Y Lan, Henry C Nguyen, Nathan D Mathewson, Irene Ni, Wei Chen, Yonghee Lee, Sindy Liao-Chan, Jessie Chen, Ton N M Schumacher, Robert D Schreiber, Yik A Yeung, Ivana M Djuretic","doi":"10.1158/2159-8290.CD-23-1266","DOIUrl":"10.1158/2159-8290.CD-23-1266","url":null,"abstract":"<p><p>IL2 signals pleiotropically on diverse cell types, some of which contribute to therapeutic activity against tumors, whereas others drive undesired activity, such as immunosuppression or toxicity. We explored the theory that targeting of IL2 to CD8+ T cells, which are key antitumor effectors, could enhance its therapeutic index. To this aim, we developed AB248, a CD8 cis-targeted IL2 that demonstrates over 500-fold preference for CD8+ T cells over natural killer and regulatory T cells (Tregs), which may contribute to toxicity and immunosuppression, respectively. AB248 recapitulated IL2's effects on CD8+ T cells in vitro and induced selective expansion of CD8+T cells in primates. In mice, an AB248 surrogate demonstrated superior antitumor activity and enhanced tolerability as compared with an untargeted IL2Rβγ agonist. Efficacy was associated with the expansion and phenotypic enhancement of tumor-infiltrating CD8+ T cells, including the emergence of a \"better effector\" population. These data support the potential utility of AB248 in clinical settings. Significance: The full potential of IL2 therapy remains to be unlocked. We demonstrate that toxicity can be decoupled from antitumor activity in preclinical models by limiting IL2 signaling to CD8+ T cells, supporting the development of CD8+ T cell-selective IL2 for the treatment of cancer. See related article by Kaptein et al. p. 1226.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11215410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140334812","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 : 2024-06-29DOI: 10.1158/2159-8290.cd-23-1249
Toby M. Baker, Siqi Lai, Andrew R. Lynch, Tom Lesluyes, Haixi Yan, Huw A. Ogilvie, Annelien Verfaillie, Stefan Dentro, Amy L. Bowes, Nischalan Pillay, Adrienne M. Flanagan, Charles Swanton, Paul T. Spellman, Maxime Tarabichi, Peter Van Loo
Tumors frequently display high chromosomal instability and contain multiple copies of genomic regions. Here, we describe GRITIC, a generic method for timing genomic gains leading to complex copy number states, using single-sample bulk whole-genome sequencing data. By applying GRITIC to 6,091 tumors, we found that non-parsimonious evolution is frequent in the formation of complex copy number states in genome-doubled tumors. We measured chromosomal instability before and after genome duplication in human tumors and found that late genome doubling was followed by an increase in the rate of copy number gain. Copy number gains often accumulate as punctuated bursts, commonly after genome doubling. We infer that genome duplications typically affect the landscape of copy number losses, while only minimally impacting copy number gains. In summary, GRITIC is a novel copy number gain timing framework that permits the analysis of copy number evolution in chromosomally unstable tumors.
{"title":"The history of chromosomal instability in genome doubled tumors","authors":"Toby M. Baker, Siqi Lai, Andrew R. Lynch, Tom Lesluyes, Haixi Yan, Huw A. Ogilvie, Annelien Verfaillie, Stefan Dentro, Amy L. Bowes, Nischalan Pillay, Adrienne M. Flanagan, Charles Swanton, Paul T. Spellman, Maxime Tarabichi, Peter Van Loo","doi":"10.1158/2159-8290.cd-23-1249","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-23-1249","url":null,"abstract":"Tumors frequently display high chromosomal instability and contain multiple copies of genomic regions. Here, we describe GRITIC, a generic method for timing genomic gains leading to complex copy number states, using single-sample bulk whole-genome sequencing data. By applying GRITIC to 6,091 tumors, we found that non-parsimonious evolution is frequent in the formation of complex copy number states in genome-doubled tumors. We measured chromosomal instability before and after genome duplication in human tumors and found that late genome doubling was followed by an increase in the rate of copy number gain. Copy number gains often accumulate as punctuated bursts, commonly after genome doubling. We infer that genome duplications typically affect the landscape of copy number losses, while only minimally impacting copy number gains. In summary, GRITIC is a novel copy number gain timing framework that permits the analysis of copy number evolution in chromosomally unstable tumors.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":28.2,"publicationDate":"2024-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141463910","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 : 2024-06-03DOI: 10.1158/2159-8290.CD-23-0996
Madison Darmofal, Shalabh Suman, Gurnit Atwal, Michael Toomey, Jie-Fu Chen, Jason C Chang, Efsevia Vakiani, Anna M Varghese, Anoop Balakrishnan Rema, Aijazuddin Syed, Nikolaus Schultz, Michael F Berger, Quaid Morris
Tumor type guides clinical treatment decisions in cancer, but histology-based diagnosis remains challenging. Genomic alterations are highly diagnostic of tumor type, and tumor-type classifiers trained on genomic features have been explored, but the most accurate methods are not clinically feasible, relying on features derived from whole-genome sequencing (WGS), or predicting across limited cancer types. We use genomic features from a data set of 39,787 solid tumors sequenced using a clinically targeted cancer gene panel to develop Genome-Derived-Diagnosis Ensemble (GDD-ENS): a hyperparameter ensemble for classifying tumor type using deep neural networks. GDD-ENS achieves 93% accuracy for high-confidence predictions across 38 cancer types, rivaling the performance of WGS-based methods. GDD-ENS can also guide diagnoses of rare type and cancers of unknown primary and incorporate patient-specific clinical information for improved predictions. Overall, integrating GDD-ENS into prospective clinical sequencing workflows could provide clinically relevant tumor-type predictions to guide treatment decisions in real time.
Significance: We describe a highly accurate tumor-type prediction model, designed specifically for clinical implementation. Our model relies only on widely used cancer gene panel sequencing data, predicts across 38 distinct cancer types, and supports integration of patient-specific nongenomic information for enhanced decision support in challenging diagnostic situations. See related commentary by Garg, p. 906. This article is featured in Selected Articles from This Issue, p. 897.
{"title":"Deep-Learning Model for Tumor-Type Prediction Using Targeted Clinical Genomic Sequencing Data.","authors":"Madison Darmofal, Shalabh Suman, Gurnit Atwal, Michael Toomey, Jie-Fu Chen, Jason C Chang, Efsevia Vakiani, Anna M Varghese, Anoop Balakrishnan Rema, Aijazuddin Syed, Nikolaus Schultz, Michael F Berger, Quaid Morris","doi":"10.1158/2159-8290.CD-23-0996","DOIUrl":"10.1158/2159-8290.CD-23-0996","url":null,"abstract":"<p><p>Tumor type guides clinical treatment decisions in cancer, but histology-based diagnosis remains challenging. Genomic alterations are highly diagnostic of tumor type, and tumor-type classifiers trained on genomic features have been explored, but the most accurate methods are not clinically feasible, relying on features derived from whole-genome sequencing (WGS), or predicting across limited cancer types. We use genomic features from a data set of 39,787 solid tumors sequenced using a clinically targeted cancer gene panel to develop Genome-Derived-Diagnosis Ensemble (GDD-ENS): a hyperparameter ensemble for classifying tumor type using deep neural networks. GDD-ENS achieves 93% accuracy for high-confidence predictions across 38 cancer types, rivaling the performance of WGS-based methods. GDD-ENS can also guide diagnoses of rare type and cancers of unknown primary and incorporate patient-specific clinical information for improved predictions. Overall, integrating GDD-ENS into prospective clinical sequencing workflows could provide clinically relevant tumor-type predictions to guide treatment decisions in real time.</p><p><strong>Significance: </strong>We describe a highly accurate tumor-type prediction model, designed specifically for clinical implementation. Our model relies only on widely used cancer gene panel sequencing data, predicts across 38 distinct cancer types, and supports integration of patient-specific nongenomic information for enhanced decision support in challenging diagnostic situations. See related commentary by Garg, p. 906. This article is featured in Selected Articles from This Issue, p. 897.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11145170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139982432","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}