Pub Date : 2024-10-04DOI: 10.1158/2159-8290.CD-23-1459
Abrar Choudhury, Martha A Cady, Calixto-Hope G Lucas, Hinda Najem, Joanna J Phillips, Brisa Palikuqi, Naomi Zakimi, Tara Joseph, Janeth O Birrueta, William C Chen, Nancy A Oberheim Bush, Shawn L Hervey-Jumper, Ophir D Klein, Christine M Toedebusch, Craig M Horbinski, Stephen T Magill, Aparna Bhaduri, Arie Perry, Peter J Dickinson, Amy B Heimberger, Alan Ashworth, Elizabeth E Crouch, David R Raleigh
Meningiomas are the most common primary intracranial tumors. Treatments for patients with meningiomas are limited to surgery and radiotherapy, and systemic therapies remain ineffective or experimental. Resistance to radiotherapy is common in high-grade meningiomas and the cell types and signaling mechanisms that drive meningioma tumorigenesis and resistance to radiotherapy are incompletely understood. Here, we report that NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy and find that perivascular NOTCH3+ stem cells are conserved across meningiomas from humans, dogs, and mice. Integrating single-cell transcriptomics with lineage tracing and imaging approaches in genetically engineered mouse models and xenografts, we show NOTCH3 drives tumor-initiating capacity, cell proliferation, angiogenesis, and resistance to radiotherapy to increase meningioma growth and reduce survival. To translate these findings to patients, we show that an antibody stabilizing the extracellular negative regulatory region of NOTCH3 blocks meningioma tumorigenesis and sensitizes meningiomas to radiotherapy, reducing tumor growth and improving survival. Significance: There are no effective systemic therapies to treat meningiomas, and meningioma stem cells are poorly understood. Here, we report perivascular NOTCH3+ stem cells to drive meningioma tumorigenesis and resistance to radiotherapy. Our results identify a conserved mechanism and a therapeutic vulnerability to treat meningiomas that are resistant to standard interventions.
{"title":"Perivascular NOTCH3+ Stem Cells Drive Meningioma Tumorigenesis and Resistance to Radiotherapy.","authors":"Abrar Choudhury, Martha A Cady, Calixto-Hope G Lucas, Hinda Najem, Joanna J Phillips, Brisa Palikuqi, Naomi Zakimi, Tara Joseph, Janeth O Birrueta, William C Chen, Nancy A Oberheim Bush, Shawn L Hervey-Jumper, Ophir D Klein, Christine M Toedebusch, Craig M Horbinski, Stephen T Magill, Aparna Bhaduri, Arie Perry, Peter J Dickinson, Amy B Heimberger, Alan Ashworth, Elizabeth E Crouch, David R Raleigh","doi":"10.1158/2159-8290.CD-23-1459","DOIUrl":"10.1158/2159-8290.CD-23-1459","url":null,"abstract":"<p><p>Meningiomas are the most common primary intracranial tumors. Treatments for patients with meningiomas are limited to surgery and radiotherapy, and systemic therapies remain ineffective or experimental. Resistance to radiotherapy is common in high-grade meningiomas and the cell types and signaling mechanisms that drive meningioma tumorigenesis and resistance to radiotherapy are incompletely understood. Here, we report that NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy and find that perivascular NOTCH3+ stem cells are conserved across meningiomas from humans, dogs, and mice. Integrating single-cell transcriptomics with lineage tracing and imaging approaches in genetically engineered mouse models and xenografts, we show NOTCH3 drives tumor-initiating capacity, cell proliferation, angiogenesis, and resistance to radiotherapy to increase meningioma growth and reduce survival. To translate these findings to patients, we show that an antibody stabilizing the extracellular negative regulatory region of NOTCH3 blocks meningioma tumorigenesis and sensitizes meningiomas to radiotherapy, reducing tumor growth and improving survival. Significance: There are no effective systemic therapies to treat meningiomas, and meningioma stem cells are poorly understood. Here, we report perivascular NOTCH3+ stem cells to drive meningioma tumorigenesis and resistance to radiotherapy. Our results identify a conserved mechanism and a therapeutic vulnerability to treat meningiomas that are resistant to standard interventions.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920963","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 : 2024-10-04DOI: 10.1158/2159-8290.CD-23-1332
Ryan N Serio, Armin Scheben, Billy Lu, Domenic V Gargiulo, Lucrezia Patruno, Caroline L Buckholtz, Ryan J Chaffee, Megan C Jibilian, Steven G Persaud, Stephen J Staklinski, Rebecca Hassett, Lise M Brault, Daniele Ramazzotti, Christopher E Barbieri, Adam C Siepel, Dawid G Nowak
The patterns by which primary tumors spread to metastatic sites remain poorly understood. Here, we define patterns of metastatic seeding in prostate cancer using a novel injection-based mouse model-EvoCaP (Evolution in Cancer of the Prostate), featuring aggressive metastatic cancer to bone, liver, lungs, and lymph nodes. To define migration histories between primary and metastatic sites, we used our EvoTraceR pipeline to track distinct tumor clones containing recordable barcodes. We detected widespread intratumoral heterogeneity from the primary tumor in metastatic seeding, with few clonal populations instigating most migration. Metastasis-to-metastasis seeding was uncommon, as most cells remained confined within the tissue. Migration patterns in our model were congruent with human prostate cancer seeding topologies. Our findings support the view of metastatic prostate cancer as a systemic disease driven by waves of aggressive clones expanding their niche, infrequently overcoming constraints that otherwise keep them confined in the primary or metastatic site. Significance: Defining the kinetics of prostate cancer metastasis is critical for developing novel therapeutic strategies. This study uses CRISPR/Cas9-based barcoding technology to accurately define tumor clonal patterns and routes of migration in a novel somatically engineered mouse model (EvoCaP) that recapitulates human prostate cancer using an in-house developed analytical pipeline (EvoTraceR).
{"title":"Clonal Lineage Tracing with Somatic Delivery of Recordable Barcodes Reveals Migration Histories of Metastatic Prostate Cancer.","authors":"Ryan N Serio, Armin Scheben, Billy Lu, Domenic V Gargiulo, Lucrezia Patruno, Caroline L Buckholtz, Ryan J Chaffee, Megan C Jibilian, Steven G Persaud, Stephen J Staklinski, Rebecca Hassett, Lise M Brault, Daniele Ramazzotti, Christopher E Barbieri, Adam C Siepel, Dawid G Nowak","doi":"10.1158/2159-8290.CD-23-1332","DOIUrl":"10.1158/2159-8290.CD-23-1332","url":null,"abstract":"<p><p>The patterns by which primary tumors spread to metastatic sites remain poorly understood. Here, we define patterns of metastatic seeding in prostate cancer using a novel injection-based mouse model-EvoCaP (Evolution in Cancer of the Prostate), featuring aggressive metastatic cancer to bone, liver, lungs, and lymph nodes. To define migration histories between primary and metastatic sites, we used our EvoTraceR pipeline to track distinct tumor clones containing recordable barcodes. We detected widespread intratumoral heterogeneity from the primary tumor in metastatic seeding, with few clonal populations instigating most migration. Metastasis-to-metastasis seeding was uncommon, as most cells remained confined within the tissue. Migration patterns in our model were congruent with human prostate cancer seeding topologies. Our findings support the view of metastatic prostate cancer as a systemic disease driven by waves of aggressive clones expanding their niche, infrequently overcoming constraints that otherwise keep them confined in the primary or metastatic site. Significance: Defining the kinetics of prostate cancer metastasis is critical for developing novel therapeutic strategies. This study uses CRISPR/Cas9-based barcoding technology to accurately define tumor clonal patterns and routes of migration in a novel somatically engineered mouse model (EvoCaP) that recapitulates human prostate cancer using an in-house developed analytical pipeline (EvoTraceR).</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537637","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 : 2024-10-04DOI: 10.1158/2159-8290.CD-24-0096
Sunil Acharya, Rafet Basar, May Daher, Hind Rafei, Ping Li, Nadima Uprety, Emily Ensley, Mayra Shanley, Bijender Kumar, Pinaki P Banerjee, Luciana Melo Garcia, Paul Lin, Vakul Mohanty, Kun H Kim, Xianli Jiang, Yuchen Pan, Ye Li, Bin Liu, Ana K Nunez Cortes, Chenyu Zhang, Mohsen Fathi, Ali Rezvan, Melisa J Montalvo, Sophia L Cha, Francia Reyes-Silva, Rejeena Shrestha, Xingliang Guo, Kiran Kundu, Alexander Biederstädt, Luis Muniz-Feliciano, Gary M Deyter, Mecit Kaplan, Xin R Jiang, Enli Liu, Antrix Jain, Janos Roszik, Natalie W Fowlkes, Luisa M Solis Soto, Maria G Raso, Joseph D Khoury, Pei Lin, Francisco Vega, Navin Varadarajan, Ken Chen, David Marin, Elizabeth J Shpall, Katayoun Rezvani
Multiple factors in the design of a chimeric antigen receptor (CAR) influence CAR T-cell activity, with costimulatory signals being a key component. Yet, the impact of costimulatory domains on the downstream signaling and subsequent functionality of CAR-engineered natural killer (NK) cells remains largely unexplored. Here, we evaluated the impact of various costimulatory domains on CAR-NK cell activity, using a CD70-targeting CAR. We found that CD28, a costimulatory molecule not inherently present in mature NK cells, significantly enhanced the antitumor efficacy and long-term cytotoxicity of CAR-NK cells both in vitro and in multiple xenograft models of hematologic and solid tumors. Mechanistically, we showed that CD28 linked to CD3ζ creates a platform that recruits critical kinases, such as lymphocyte-specific protein tyrosine kinase (LCK) and zeta-chain-associated protein kinase 70 (ZAP70), initiating a signaling cascade that enhances CAR-NK cell function. Our study provides insights into how CD28 costimulation enhances CAR-NK cell function and supports its incorporation in NK-based CARs for cancer immunotherapy. Significance: We demonstrated that incorporation of the T-cell-centric costimulatory molecule CD28, which is normally absent in mature natural killer (NK) cells, into the chimeric antigen receptor (CAR) construct recruits key kinases including lymphocyte-specific protein tyrosine kinase and zeta-chain-associated protein kinase 70 and results in enhanced CAR-NK cell persistence and sustained antitumor cytotoxicity.
嵌合抗原受体(CAR)设计中的多种因素会影响 CAR T 细胞的活性,其中成本调控信号是一个关键因素。然而,成本调控域对 CAR 工程自然杀伤(NK)细胞的下游信号转导和后续功能的影响在很大程度上仍未得到探讨。在这里,我们使用一种 CD70 靶向 CAR 评估了各种成本调控域对 CAR-NK 细胞活性的影响。我们发现,CD28是成熟NK细胞中并不固有的一种协同调控分子,它能显著增强CAR-NK细胞在体外以及多种血液肿瘤和实体瘤异种移植模型中的抗肿瘤疗效和长期细胞毒性。从机理上讲,我们发现 CD28 与 CD3Z 连接形成了一个平台,它能招募 LCK 和 ZAP70 等关键激酶,启动信号级联,增强 CAR-NK 细胞的功能。我们的研究深入揭示了 CD28 成本刺激如何增强 CAR-NK 细胞功能,并支持将其纳入基于 NK 的 CAR 用于癌症免疫疗法。
{"title":"CD28 Costimulation Augments CAR Signaling in NK Cells via the LCK/CD3ζ/ZAP70 Signaling Axis.","authors":"Sunil Acharya, Rafet Basar, May Daher, Hind Rafei, Ping Li, Nadima Uprety, Emily Ensley, Mayra Shanley, Bijender Kumar, Pinaki P Banerjee, Luciana Melo Garcia, Paul Lin, Vakul Mohanty, Kun H Kim, Xianli Jiang, Yuchen Pan, Ye Li, Bin Liu, Ana K Nunez Cortes, Chenyu Zhang, Mohsen Fathi, Ali Rezvan, Melisa J Montalvo, Sophia L Cha, Francia Reyes-Silva, Rejeena Shrestha, Xingliang Guo, Kiran Kundu, Alexander Biederstädt, Luis Muniz-Feliciano, Gary M Deyter, Mecit Kaplan, Xin R Jiang, Enli Liu, Antrix Jain, Janos Roszik, Natalie W Fowlkes, Luisa M Solis Soto, Maria G Raso, Joseph D Khoury, Pei Lin, Francisco Vega, Navin Varadarajan, Ken Chen, David Marin, Elizabeth J Shpall, Katayoun Rezvani","doi":"10.1158/2159-8290.CD-24-0096","DOIUrl":"10.1158/2159-8290.CD-24-0096","url":null,"abstract":"<p><p>Multiple factors in the design of a chimeric antigen receptor (CAR) influence CAR T-cell activity, with costimulatory signals being a key component. Yet, the impact of costimulatory domains on the downstream signaling and subsequent functionality of CAR-engineered natural killer (NK) cells remains largely unexplored. Here, we evaluated the impact of various costimulatory domains on CAR-NK cell activity, using a CD70-targeting CAR. We found that CD28, a costimulatory molecule not inherently present in mature NK cells, significantly enhanced the antitumor efficacy and long-term cytotoxicity of CAR-NK cells both in vitro and in multiple xenograft models of hematologic and solid tumors. Mechanistically, we showed that CD28 linked to CD3ζ creates a platform that recruits critical kinases, such as lymphocyte-specific protein tyrosine kinase (LCK) and zeta-chain-associated protein kinase 70 (ZAP70), initiating a signaling cascade that enhances CAR-NK cell function. Our study provides insights into how CD28 costimulation enhances CAR-NK cell function and supports its incorporation in NK-based CARs for cancer immunotherapy. Significance: We demonstrated that incorporation of the T-cell-centric costimulatory molecule CD28, which is normally absent in mature natural killer (NK) cells, into the chimeric antigen receptor (CAR) construct recruits key kinases including lymphocyte-specific protein tyrosine kinase and zeta-chain-associated protein kinase 70 and results in enhanced CAR-NK cell persistence and sustained antitumor cytotoxicity.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426394","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 : 2024-10-04DOI: 10.1158/2159-8290.CD-24-0100
Katelyn L Donahue, Hannah R Watkoske, Padma Kadiyala, Wenting Du, Kristee Brown, Michael K Scales, Ahmed M Elhossiny, Carlos E Espinoza, Emily L Lasse Opsahl, Brian D Griffith, Yukang Wen, Lei Sun, Ashley Velez-Delgado, Nur M Renollet, Jacqueline Morales, Nicholas M Nedzesky, Rachael K Baliira, Rosa E Menjivar, Paola I Medina-Cabrera, Arvind Rao, Benjamin Allen, Jiaqi Shi, Timothy L Frankel, Eileen S Carpenter, Filip Bednar, Yaqing Zhang, Marina Pasca di Magliano
Pancreatic cancer is characterized by an extensive fibroinflammatory microenvironment. During carcinogenesis, normal stromal cells are converted to cytokine-high cancer-associated fibroblasts (CAF). The mechanisms underlying this conversion, including the regulation and function of fibroblast-derived cytokines, are poorly understood. Thus, efforts to therapeutically target CAFs have so far failed. Herein, we show that signals from epithelial cells expressing oncogenic KRAS-a hallmark pancreatic cancer mutation-activate fibroblast autocrine signaling, which drives the expression of the cytokine IL33. Stromal IL33 expression remains high and dependent on epithelial KRAS throughout carcinogenesis; in turn, environmental stress induces interleukin-33 (IL33) secretion. Using compartment-specific IL33 knockout mice, we observed that lack of stromal IL33 leads to profound reprogramming of multiple components of the pancreatic tumor microenvironment, including CAFs, myeloid cells, and lymphocytes. Notably, loss of stromal IL33 leads to an increase in CD8+ T-cell infiltration and activation and, ultimately, reduced tumor growth. Significance: This study provides new insights into the mechanisms underlying the programming of CAFs and shows that during this process, expression of the cytokine IL33 is induced. CAF-derived IL33 has pleiotropic effects on the tumor microenvironment, supporting its potential as a therapeutic target.
{"title":"Oncogenic KRAS-Dependent Stromal Interleukin-33 Directs the Pancreatic Microenvironment to Promote Tumor Growth.","authors":"Katelyn L Donahue, Hannah R Watkoske, Padma Kadiyala, Wenting Du, Kristee Brown, Michael K Scales, Ahmed M Elhossiny, Carlos E Espinoza, Emily L Lasse Opsahl, Brian D Griffith, Yukang Wen, Lei Sun, Ashley Velez-Delgado, Nur M Renollet, Jacqueline Morales, Nicholas M Nedzesky, Rachael K Baliira, Rosa E Menjivar, Paola I Medina-Cabrera, Arvind Rao, Benjamin Allen, Jiaqi Shi, Timothy L Frankel, Eileen S Carpenter, Filip Bednar, Yaqing Zhang, Marina Pasca di Magliano","doi":"10.1158/2159-8290.CD-24-0100","DOIUrl":"10.1158/2159-8290.CD-24-0100","url":null,"abstract":"<p><p>Pancreatic cancer is characterized by an extensive fibroinflammatory microenvironment. During carcinogenesis, normal stromal cells are converted to cytokine-high cancer-associated fibroblasts (CAF). The mechanisms underlying this conversion, including the regulation and function of fibroblast-derived cytokines, are poorly understood. Thus, efforts to therapeutically target CAFs have so far failed. Herein, we show that signals from epithelial cells expressing oncogenic KRAS-a hallmark pancreatic cancer mutation-activate fibroblast autocrine signaling, which drives the expression of the cytokine IL33. Stromal IL33 expression remains high and dependent on epithelial KRAS throughout carcinogenesis; in turn, environmental stress induces interleukin-33 (IL33) secretion. Using compartment-specific IL33 knockout mice, we observed that lack of stromal IL33 leads to profound reprogramming of multiple components of the pancreatic tumor microenvironment, including CAFs, myeloid cells, and lymphocytes. Notably, loss of stromal IL33 leads to an increase in CD8+ T-cell infiltration and activation and, ultimately, reduced tumor growth. Significance: This study provides new insights into the mechanisms underlying the programming of CAFs and shows that during this process, expression of the cytokine IL33 is induced. CAF-derived IL33 has pleiotropic effects on the tumor microenvironment, supporting its potential as a therapeutic target.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490962","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 : 2024-10-02DOI: 10.1158/2159-8290.CD-24-0134
Neibla Priego, Ana de Pablos-Aragoneses, Maria Perea-García, Valentina Pieri, Carolina Hernandez-Oliver, Laura Alvaro-Espinosa, Andrea Rojas, Oliva Sanchez, Ariane Steindl, Eduardo Caleiras, Fernando Garcia, Santiago Garcia-Martin, Osvaldo Grana-Castro, Sandra Garcia-Mulero, Diego Serrano, Paloma Velasco-Beltran, Borja Jimenez-Lasheras, Leire Egia-Mendikute, Luise Rupp, Antonia Stammberger, Matthias Meinhardt, Anas Chaachou-Charradi, Elena Martínez-Saez, Luca Bertero, Paola Cassoni, Luca Mangherini, Alessia Pellerino, Roberta Ruda, Riccardo Soffietti, Fatima Al-Shahrour, Paul Saftig, Rebeca Sanz-Pamplona, Marc Schmitz, Stephen J Crocker, Alfonso Calvo, Asis Palazon, Renacer Group, Manuel Valiente
Immunotherapies against brain metastases have shown clinical benefits when applied to asymptomatic patients, but they are largely ineffective in symptomatic cases for unknown reasons. Here we dissect the heterogeneity in metastasis-associated astrocytes using scRNAseq and report a population that blocks the antitumoral activity of infiltrating T cells. This pro-tumoral activity is mediated by the secretion of TIMP1 from a cluster of pSTAT3+ astrocytes that acts on CD63+ CD8+ T cells to modulate their function. Using genetic and pharmacologic approaches in mouse and human brain metastasis models, we demonstrate that combining immune checkpoint blockade antibodies with the inhibition of astrocyte-mediated local immunosuppression may benefit patients with symptomatic brain metastases. We further reveal that the presence of TIMP1 in liquid biopsies provides a biomarker to select patients for this combined immunotherapy. Overall, our findings demonstrate an unexpected immunomodulatory role for astrocytes in brain metastases with clinical implications.
针对脑转移瘤的免疫疗法在应用于无症状患者时已显示出临床疗效,但在有症状的病例中却大多无效,原因不明。在这里,我们利用 scRNAseq 对转移相关星形胶质细胞的异质性进行了剖析,并报告了一个阻止浸润 T 细胞抗肿瘤活性的群体。这种促肿瘤活性是由一组 pSTAT3+ 星形胶质细胞分泌的 TIMP1 介导的,TIMP1 作用于 CD63+ CD8+ T 细胞以调节其功能。通过在小鼠和人类脑转移模型中使用基因和药理学方法,我们证明将免疫检查点阻断抗体与抑制星形胶质细胞介导的局部免疫抑制相结合,可能会使有症状的脑转移患者受益。我们进一步发现,液体活检中 TIMP1 的存在为选择接受这种联合免疫疗法的患者提供了一种生物标志物。总之,我们的研究结果表明,星形胶质细胞在脑转移瘤中发挥着意想不到的免疫调节作用,并具有临床意义。
{"title":"TIMP1 mediates astrocyte-dependent local immunosuppression in brain metastasis acting on infiltrating CD8+ T cells.","authors":"Neibla Priego, Ana de Pablos-Aragoneses, Maria Perea-García, Valentina Pieri, Carolina Hernandez-Oliver, Laura Alvaro-Espinosa, Andrea Rojas, Oliva Sanchez, Ariane Steindl, Eduardo Caleiras, Fernando Garcia, Santiago Garcia-Martin, Osvaldo Grana-Castro, Sandra Garcia-Mulero, Diego Serrano, Paloma Velasco-Beltran, Borja Jimenez-Lasheras, Leire Egia-Mendikute, Luise Rupp, Antonia Stammberger, Matthias Meinhardt, Anas Chaachou-Charradi, Elena Martínez-Saez, Luca Bertero, Paola Cassoni, Luca Mangherini, Alessia Pellerino, Roberta Ruda, Riccardo Soffietti, Fatima Al-Shahrour, Paul Saftig, Rebeca Sanz-Pamplona, Marc Schmitz, Stephen J Crocker, Alfonso Calvo, Asis Palazon, Renacer Group, Manuel Valiente","doi":"10.1158/2159-8290.CD-24-0134","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0134","url":null,"abstract":"<p><p>Immunotherapies against brain metastases have shown clinical benefits when applied to asymptomatic patients, but they are largely ineffective in symptomatic cases for unknown reasons. Here we dissect the heterogeneity in metastasis-associated astrocytes using scRNAseq and report a population that blocks the antitumoral activity of infiltrating T cells. This pro-tumoral activity is mediated by the secretion of TIMP1 from a cluster of pSTAT3+ astrocytes that acts on CD63+ CD8+ T cells to modulate their function. Using genetic and pharmacologic approaches in mouse and human brain metastasis models, we demonstrate that combining immune checkpoint blockade antibodies with the inhibition of astrocyte-mediated local immunosuppression may benefit patients with symptomatic brain metastases. We further reveal that the presence of TIMP1 in liquid biopsies provides a biomarker to select patients for this combined immunotherapy. Overall, our findings demonstrate an unexpected immunomodulatory role for astrocytes in brain metastases with clinical implications.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142361163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1158/2159-8290.CD-24-0489
Yonghong Liu, Jincheng Han, Wen-Hao Hsu, Kyle A LaBella, Pingna Deng, Xiaoying Shang, Paulino Tallon de Lara, Li Cai, Shan Jiang, Ronald A DePinho
Pancreatic ductal adenocarcinoma (PDAC) resists conventional chemo/radiation and immunotherapy. In PDAC, oncogenic KRAS (KRAS*) drives glycolysis in cancer cells to consume available glucose and produce abundant lactate, creating profound immune suppression in the tumor microenvironment. Here, we combined KRAS* inhibition with agents targeting the major arms of the immunity cycle: CXCR1/2 inhibitor for myeloid cells, antagonistic anti-LAG3 antibody for T cells, and agonistic anti-41BB antibody for dendritic cells. This combination elicited robust anti-tumor regression in iKPC mice bearing large autochthonous tumors. While untreated mice succumbed within 3 weeks, sustained treatment led to durable complete tumor regression and prolonged survival in 36% of mice at 6 months. Mechanistic analyses revealed enhanced T cell infiltration and activation, depletion of immunosuppressive myeloid cells, and increased antigen cross-presentation by dendritic cells within the tumor core. These findings highlight the promise of KRAS* inhibitors alongside immunotherapy as a potential PDAC treatment avenue, warranting clinical investigation.
{"title":"Combined KRAS inhibition and immune therapy generates durable complete responses in an autochthonous PDAC model.","authors":"Yonghong Liu, Jincheng Han, Wen-Hao Hsu, Kyle A LaBella, Pingna Deng, Xiaoying Shang, Paulino Tallon de Lara, Li Cai, Shan Jiang, Ronald A DePinho","doi":"10.1158/2159-8290.CD-24-0489","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0489","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) resists conventional chemo/radiation and immunotherapy. In PDAC, oncogenic KRAS (KRAS*) drives glycolysis in cancer cells to consume available glucose and produce abundant lactate, creating profound immune suppression in the tumor microenvironment. Here, we combined KRAS* inhibition with agents targeting the major arms of the immunity cycle: CXCR1/2 inhibitor for myeloid cells, antagonistic anti-LAG3 antibody for T cells, and agonistic anti-41BB antibody for dendritic cells. This combination elicited robust anti-tumor regression in iKPC mice bearing large autochthonous tumors. While untreated mice succumbed within 3 weeks, sustained treatment led to durable complete tumor regression and prolonged survival in 36% of mice at 6 months. Mechanistic analyses revealed enhanced T cell infiltration and activation, depletion of immunosuppressive myeloid cells, and increased antigen cross-presentation by dendritic cells within the tumor core. These findings highlight the promise of KRAS* inhibitors alongside immunotherapy as a potential PDAC treatment avenue, warranting clinical investigation.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1158/2159-8290.cd-24-0393
Jamie E. Medina, Akshaya V. Annapragada, Pien Lof, Sarah Short, Adrianna L. Bartolomucci, Dimitrios Mathios, Shashikant Koul, Noushin Niknafs, Michael Noe, Zachariah H. Foda, Daniel C. Bruhm, Carolyn Hruban, Nicholas A. Vulpescu, Euihye Jung, Renu Dua, Jenna V. Canzoniero, Stephen Cristiano, Vilmos Adleff, Heather Symecko, Daan van den Broek, Lori J. Sokoll, Stephen B. Baylin, Michael F. Press, Dennis J. Slamon, Gottfried E. Konecny, Christina Therkildsen, Beatriz Carvalho, Gerrit A. Meijer, Claus Lindbjerg. Andersen, Susan M. Domchek, Ronny Drapkin, Robert B. Scharpf, Jillian Phallen, Christine A.R. Lok, Victor E. Velculescu
Ovarian cancer is a leading cause of death for women worldwide in part due to ineffective screening methods. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker (CA-125 and HE4) analyses to evaluate 591 women with ovarian cancer, benign adnexal masses, or without ovarian lesions. Using a machine learning model with the combined features, we detected ovarian cancer with specificity >99% and sensitivity of 72%, 69%, 87%, and 100% for stages I–IV, respectively. At the same specificity, CA-125 alone detected 34%, 62%, 63%, and 100% of ovarian cancers for stages I–IV. Our approach differentiated benign masses from ovarian cancers with high accuracy (AUC=0.88, 95% CI=0.83-0.92). These results were validated in an independent population. These findings show that integrated cfDNA fragmentome and protein analyses detect ovarian cancers with high performance, enabling a new accessible approach for noninvasive ovarian cancer screening and diagnostic evaluation.
{"title":"Early detection of ovarian cancer using cell-free DNA fragmentomes and protein biomarkers","authors":"Jamie E. Medina, Akshaya V. Annapragada, Pien Lof, Sarah Short, Adrianna L. Bartolomucci, Dimitrios Mathios, Shashikant Koul, Noushin Niknafs, Michael Noe, Zachariah H. Foda, Daniel C. Bruhm, Carolyn Hruban, Nicholas A. Vulpescu, Euihye Jung, Renu Dua, Jenna V. Canzoniero, Stephen Cristiano, Vilmos Adleff, Heather Symecko, Daan van den Broek, Lori J. Sokoll, Stephen B. Baylin, Michael F. Press, Dennis J. Slamon, Gottfried E. Konecny, Christina Therkildsen, Beatriz Carvalho, Gerrit A. Meijer, Claus Lindbjerg. Andersen, Susan M. Domchek, Ronny Drapkin, Robert B. Scharpf, Jillian Phallen, Christine A.R. Lok, Victor E. Velculescu","doi":"10.1158/2159-8290.cd-24-0393","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0393","url":null,"abstract":"Ovarian cancer is a leading cause of death for women worldwide in part due to ineffective screening methods. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker (CA-125 and HE4) analyses to evaluate 591 women with ovarian cancer, benign adnexal masses, or without ovarian lesions. Using a machine learning model with the combined features, we detected ovarian cancer with specificity &gt;99% and sensitivity of 72%, 69%, 87%, and 100% for stages I–IV, respectively. At the same specificity, CA-125 alone detected 34%, 62%, 63%, and 100% of ovarian cancers for stages I–IV. Our approach differentiated benign masses from ovarian cancers with high accuracy (AUC=0.88, 95% CI=0.83-0.92). These results were validated in an independent population. These findings show that integrated cfDNA fragmentome and protein analyses detect ovarian cancers with high performance, enabling a new accessible approach for noninvasive ovarian cancer screening and diagnostic evaluation.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":28.2,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-26DOI: 10.1158/2159-8290.cd-24-0634
Ilaria Gritti, Jinkai Wan, Vajira Weeresekara, Joel M. Vaz, Giuseppe Tarantino, Tenna Holgersen. Bryde, Vindhya Vijay, Ashwin V. Kammula, Prabhat Kattel, Songli Zhu, Phuong Vu, Marina Chan, Meng-Ju Wu, John D. Gordan, Krushna C. Patra, Vanessa S. Silveira, Robert T. Manguso, Marc N. Wein, Christopher J. Ott, Jun Qi, David Liu, Kei Sakamoto, Taranjit S. Gujral, Nabeel Bardeesy
Fibrolamellar carcinoma (FLC) is a liver cancer of adolescents and young adults characterized by fusions of the genes encoding the protein kinase A catalytic subunit, PRKACA, and heat shock protein, DNAJB1. The chimeric DNAJB1-PRKACA protein has increased kinase activity and is essential for FLC xenograft growth. Here, we explore the critical oncogenic pathways controlled by DNAJB1-PRKACA using patient-derived FLC models, engineered systems, and patient samples. We show that a core function of DNAJB1-PRKACA is the phosphorylation and inactivation of Salt-inducible kinases (SIKs). This leads to deregulation of the CRTC2 transcriptional co-activator and p300 acetyltransferase, resulting in transcriptional reprogramming and increased global histone acetylation, driving malignant growth. Our studies establish a central oncogenic mechanism of DNAJB1-PRKACA and suggest the potential of targeting CRTC2/p300 in FLC. Notably, these findings link this rare cancer’s signature fusion oncoprotein to more common cancer gene alterations involving STK11 and GNAS, which also function via SIK suppression.
{"title":"DNAJB1-PRKACA fusion drives fibrolamellar liver cancer through impaired SIK signaling and CRTC2/p300-mediated transcriptional reprogramming","authors":"Ilaria Gritti, Jinkai Wan, Vajira Weeresekara, Joel M. Vaz, Giuseppe Tarantino, Tenna Holgersen. Bryde, Vindhya Vijay, Ashwin V. Kammula, Prabhat Kattel, Songli Zhu, Phuong Vu, Marina Chan, Meng-Ju Wu, John D. Gordan, Krushna C. Patra, Vanessa S. Silveira, Robert T. Manguso, Marc N. Wein, Christopher J. Ott, Jun Qi, David Liu, Kei Sakamoto, Taranjit S. Gujral, Nabeel Bardeesy","doi":"10.1158/2159-8290.cd-24-0634","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0634","url":null,"abstract":"Fibrolamellar carcinoma (FLC) is a liver cancer of adolescents and young adults characterized by fusions of the genes encoding the protein kinase A catalytic subunit, PRKACA, and heat shock protein, DNAJB1. The chimeric DNAJB1-PRKACA protein has increased kinase activity and is essential for FLC xenograft growth. Here, we explore the critical oncogenic pathways controlled by DNAJB1-PRKACA using patient-derived FLC models, engineered systems, and patient samples. We show that a core function of DNAJB1-PRKACA is the phosphorylation and inactivation of Salt-inducible kinases (SIKs). This leads to deregulation of the CRTC2 transcriptional co-activator and p300 acetyltransferase, resulting in transcriptional reprogramming and increased global histone acetylation, driving malignant growth. Our studies establish a central oncogenic mechanism of DNAJB1-PRKACA and suggest the potential of targeting CRTC2/p300 in FLC. Notably, these findings link this rare cancer’s signature fusion oncoprotein to more common cancer gene alterations involving STK11 and GNAS, which also function via SIK suppression.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":28.2,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-24DOI: 10.1158/2159-8290.CD-24-1288
Despite exponentially increased industry investment in oncology research and development with more than $80 billion spent annually, patient enrollment in clinical trials remains below 5% globally. Our multistakeholder international cancer coalition envisions ecosystem transformation with capacity building through a global "hub-and-spoke" network model to expand access to and accelerate clinical trials, thus ending cancer as a major cause of death in this lifetime.
{"title":"Advancing Global Health Equity in Oncology Clinical Trial Access.","authors":"","doi":"10.1158/2159-8290.CD-24-1288","DOIUrl":"10.1158/2159-8290.CD-24-1288","url":null,"abstract":"<p><p>Despite exponentially increased industry investment in oncology research and development with more than $80 billion spent annually, patient enrollment in clinical trials remains below 5% globally. Our multistakeholder international cancer coalition envisions ecosystem transformation with capacity building through a global \"hub-and-spoke\" network model to expand access to and accelerate clinical trials, thus ending cancer as a major cause of death in this lifetime.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1158/2159-8290.CD-24-0887
Brian Belmontes, Katherine K Slemmons, Chun Su, Siyuan Liu, Antonia N Policheni, Jodi Moriguchi, Hong Tan, Fang Xie, Daniel Andrew Aiello, Yajing Yang, Raul Lazaro, Famke Aeffner, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Mikkel Vestergaard, Sanne Cowland, Jan Andersson, Ian Sarvary, Qing Chen, Pooja Sharma, Patricia Lopez, Nuria Tamayo, Liping H Pettus, Sudipa Ghimire-Rijal, Susmith Mukund, Jennifer R Allen, Jason DeVoss, Angela Coxon, Jordi Rodon, Francois Ghiringhelli, Nicolas Penel, Hans Prenen, Sanne Glad, Chen-Hua Chuang, Kiana Keyvanjah, Danielle M Townsley, John R Butler, Matthew P Bourbeau, Sean Caenepeel, Paul E Hughes
One of the most robust synthetic lethal interactions observed in multiple functional genomic screens has been dependency on PRMT5 in cancer cells with MTAP deletion. We report the discovery of the clinical stage MTA-cooperative PRMT5 inhibitor AMG 193, which preferentially binds PRMT5 in the presence of MTA and has potent biochemical and cellular activity in MTAP-deleted cells across multiple cancer lineages. In vitro, PRMT5 inhibition induces DNA damage, cell cycle arrest, and aberrant alternative mRNA splicing in MTAP-deleted cells. In human cell line and patient-derived xenograft models, AMG 193 induces robust antitumor activity and is well tolerated with no impact on normal hematopoietic cell lineages. AMG 193 synergizes with chemotherapies or the KRAS G12C inhibitor sotorasib in vitro, and combination treatment in vivo significantly inhibits tumor growth. AMG 193 is demonstrating promising clinical activity, including confirmed partial responses in patients with MTAP-deleted solid tumors from an ongoing phase 1/2 study.
{"title":"AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients With MTAP-Deleted Cancers.","authors":"Brian Belmontes, Katherine K Slemmons, Chun Su, Siyuan Liu, Antonia N Policheni, Jodi Moriguchi, Hong Tan, Fang Xie, Daniel Andrew Aiello, Yajing Yang, Raul Lazaro, Famke Aeffner, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Mikkel Vestergaard, Sanne Cowland, Jan Andersson, Ian Sarvary, Qing Chen, Pooja Sharma, Patricia Lopez, Nuria Tamayo, Liping H Pettus, Sudipa Ghimire-Rijal, Susmith Mukund, Jennifer R Allen, Jason DeVoss, Angela Coxon, Jordi Rodon, Francois Ghiringhelli, Nicolas Penel, Hans Prenen, Sanne Glad, Chen-Hua Chuang, Kiana Keyvanjah, Danielle M Townsley, John R Butler, Matthew P Bourbeau, Sean Caenepeel, Paul E Hughes","doi":"10.1158/2159-8290.CD-24-0887","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0887","url":null,"abstract":"<p><p>One of the most robust synthetic lethal interactions observed in multiple functional genomic screens has been dependency on PRMT5 in cancer cells with MTAP deletion. We report the discovery of the clinical stage MTA-cooperative PRMT5 inhibitor AMG 193, which preferentially binds PRMT5 in the presence of MTA and has potent biochemical and cellular activity in MTAP-deleted cells across multiple cancer lineages. In vitro, PRMT5 inhibition induces DNA damage, cell cycle arrest, and aberrant alternative mRNA splicing in MTAP-deleted cells. In human cell line and patient-derived xenograft models, AMG 193 induces robust antitumor activity and is well tolerated with no impact on normal hematopoietic cell lineages. AMG 193 synergizes with chemotherapies or the KRAS G12C inhibitor sotorasib in vitro, and combination treatment in vivo significantly inhibits tumor growth. AMG 193 is demonstrating promising clinical activity, including confirmed partial responses in patients with MTAP-deleted solid tumors from an ongoing phase 1/2 study.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280594","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}