Hyperprogressive disease can occur in cancer patients receiving immune checkpoint blockade (ICB) therapy, but whether and how reactive cytotoxic T lymphocytes (CTLs) exert protumorigenic effects in this context remain elusive. Herein, our study reveals that pericancerous macrophages cross-present antigens to CD103+ CTLs in hepatocellular carcinoma (HCC) via the endoplasmic reticulum (ER)-associated degradation machinery-mediated cytosolic pathway. This process leads to the retention of CD103+ CTLs in the pericancerous area, whereby they activate NLRP3 inflammasome in macrophages, promoting hepatoma progression and resistance to immunotherapy. Our single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics analysis of HCC patients shows that despite their tissue-resident effector phenotype, the aggregation of CD103+ CTLs predicts unfavorable clinical outcomes for HCC patients receiving multiple types of treatment. Correspondingly, therapeutic strategies that redistribute CD103+ CTLs can disrupt this pathogenic interplay with macrophages, enhancing the efficacy of ICB treatment against HCC.
{"title":"Pericancerous cross-presentation to cytotoxic T lymphocytes impairs immunotherapeutic efficacy in hepatocellular carcinoma","authors":"Chun-Xiang Huang, Xiang-Ming Lao, Xu-Yan Wang, Yi-Zheng Ren, Yi-Tong Lu, Wei Shi, Ying-Zhe Wang, Cai-Yuan Wu, Li Xu, Min-Shan Chen, Qiang Gao, Lianxin Liu, Yuan Wei, Dong-Ming Kuang","doi":"10.1016/j.ccell.2024.10.012","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.012","url":null,"abstract":"Hyperprogressive disease can occur in cancer patients receiving immune checkpoint blockade (ICB) therapy, but whether and how reactive cytotoxic T lymphocytes (CTLs) exert protumorigenic effects in this context remain elusive. Herein, our study reveals that pericancerous macrophages cross-present antigens to CD103<sup>+</sup> CTLs in hepatocellular carcinoma (HCC) via the endoplasmic reticulum (ER)-associated degradation machinery-mediated cytosolic pathway. This process leads to the retention of CD103<sup>+</sup> CTLs in the pericancerous area, whereby they activate NLRP3 inflammasome in macrophages, promoting hepatoma progression and resistance to immunotherapy. Our single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics analysis of HCC patients shows that despite their tissue-resident effector phenotype, the aggregation of CD103<sup>+</sup> CTLs predicts unfavorable clinical outcomes for HCC patients receiving multiple types of treatment. Correspondingly, therapeutic strategies that redistribute CD103<sup>+</sup> CTLs can disrupt this pathogenic interplay with macrophages, enhancing the efficacy of ICB treatment against HCC.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"38 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-14DOI: 10.1016/j.ccell.2024.10.011
Lara Haase, Christian Frezza
Itaconate is a metabolite produced by macrophages upon infection and acts as an antimicrobial molecule. In this issue of Cancer Cell, Lin et al. found that itaconate produced by tumor-associated macrophages is taken up by cancer cells via the transporter solute carrier family 13 member 3 (SLC13A3), promoting resistance to immune checkpoint inhibitors.
{"title":"Itaconate promotes an unexpected tumor immune escape mechanism","authors":"Lara Haase, Christian Frezza","doi":"10.1016/j.ccell.2024.10.011","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.011","url":null,"abstract":"Itaconate is a metabolite produced by macrophages upon infection and acts as an antimicrobial molecule. In this issue of <em>Cancer Cell</em>, Lin et al. found that itaconate produced by tumor-associated macrophages is taken up by cancer cells via the transporter solute carrier family 13 member 3 (SLC13A3), promoting resistance to immune checkpoint inhibitors.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"20 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-11DOI: 10.1016/j.ccell.2024.10.009
Robert L. Bowman, Andrew J. Dunbar, Tanmay Mishra, Wenbin Xiao, Michael R. Waarts, Inés Fernández Maestre, Shira E. Eisman, Louise Cai, Shoron Mowla, Nisargbhai Shah, Angela Youn, Laura Bennett, Suean Fontenard, Shreeya Gounder, Anushka Gandhi, Michael Bowman, Kavi O’Connor, Zachary Zaroogian, Pablo Sánchez-Vela, Anthony R. Martinez Benitez, Ross L. Levine
Cancer evolution is a multifaceted process leading to dysregulation of cellular expansion and differentiation through somatic mutations and epigenetic dysfunction. Clonal expansion and evolution is driven by cell-intrinsic and -extrinsic selective pressures, which can be captured with increasing resolution by single-cell and bulk DNA sequencing. Despite the extensive genomic alterations revealed in profiling studies, there remain limited experimental systems to model and perturb evolutionary processes. Here, we integrate multi-recombinase tools for reversible, sequential mutagenesis from premalignancy to leukemia. We demonstrate that inducible Flt3 mutations differentially cooperate with Dnmt3a, Idh2, and Npm1 mutant alleles, and that changing the order of mutations influences cellular and transcriptional landscapes. We next use a generalizable, reversible approach to demonstrate that mutation reversion results in rapid leukemic regression with distinct differentiation patterns depending upon co-occurring mutations. These studies provide a path to experimentally model sequential mutagenesis, investigate mechanisms of transformation and probe oncogenic dependency in disease evolution.
{"title":"In vivo models of subclonal oncogenesis and dependency in hematopoietic malignancy","authors":"Robert L. Bowman, Andrew J. Dunbar, Tanmay Mishra, Wenbin Xiao, Michael R. Waarts, Inés Fernández Maestre, Shira E. Eisman, Louise Cai, Shoron Mowla, Nisargbhai Shah, Angela Youn, Laura Bennett, Suean Fontenard, Shreeya Gounder, Anushka Gandhi, Michael Bowman, Kavi O’Connor, Zachary Zaroogian, Pablo Sánchez-Vela, Anthony R. Martinez Benitez, Ross L. Levine","doi":"10.1016/j.ccell.2024.10.009","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.009","url":null,"abstract":"Cancer evolution is a multifaceted process leading to dysregulation of cellular expansion and differentiation through somatic mutations and epigenetic dysfunction. Clonal expansion and evolution is driven by cell-intrinsic and -extrinsic selective pressures, which can be captured with increasing resolution by single-cell and bulk DNA sequencing. Despite the extensive genomic alterations revealed in profiling studies, there remain limited experimental systems to model and perturb evolutionary processes. Here, we integrate multi-recombinase tools for reversible, sequential mutagenesis from premalignancy to leukemia. We demonstrate that inducible <em>Flt3</em> mutations differentially cooperate with <em>Dnmt3a</em>, <em>Idh2</em>, and <em>Npm1</em> mutant alleles, and that changing the order of mutations influences cellular and transcriptional landscapes. We next use a generalizable, reversible approach to demonstrate that mutation reversion results in rapid leukemic regression with distinct differentiation patterns depending upon co-occurring mutations. These studies provide a path to experimentally model sequential mutagenesis, investigate mechanisms of transformation and probe oncogenic dependency in disease evolution.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"41 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-11DOI: 10.1016/j.ccell.2024.10.013
Rei Kudo, Anton Safonov, Catherine Jones, Enrico Moiso, Jonathan R. Dry, Hong Shao, Sharanya Nag, Edaise M. da Silva, Selma Yeni Yildirim, Qing Li, Elizabeth O’Connell, Payal Patel, Marie Will, Atsushi Fushimi, Marimar Benitez, Martina Bradic, Li Fan, Harikrishna Nakshatri, Dhivya R. Sudhan, Christopher R. Denz, Sarat Chandarlapaty
(Cancer Cell 42, 1919–1935.e9; November 11, 2024)
(癌症细胞》第 42 期，1919-1935.e9；2024 年 11 月 11 日）
{"title":"Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion","authors":"Rei Kudo, Anton Safonov, Catherine Jones, Enrico Moiso, Jonathan R. Dry, Hong Shao, Sharanya Nag, Edaise M. da Silva, Selma Yeni Yildirim, Qing Li, Elizabeth O’Connell, Payal Patel, Marie Will, Atsushi Fushimi, Marimar Benitez, Martina Bradic, Li Fan, Harikrishna Nakshatri, Dhivya R. Sudhan, Christopher R. Denz, Sarat Chandarlapaty","doi":"10.1016/j.ccell.2024.10.013","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.013","url":null,"abstract":"(Cancer Cell <em>42</em>, 1919–1935.e9; November 11, 2024)","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"61 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07DOI: 10.1016/j.ccell.2024.10.008
Chen Yang, Haigang Geng, Xupeng Yang, Shuyi Ji, Zhicheng Liu, Hao Feng, Qian Li, Tangansu Zhang, Sisi Zhang, Xuhui Ma, Chuchen Zhu, Nuo Xu, Yuhan Xia, Yan Li, Hongye Wang, Chune Yu, Shangce Du, Beiping Miao, Lei Xu, Hui Wang, Cun Wang
Tumor-initiating cells (TICs) possess the ability to evade anti-tumor immunity, potentially explaining many failures of cancer immunotherapy. Here, we identify CD49f as a prominent marker for discerning TICs in hepatocellular carcinoma (HCC), outperforming other commonly used TIC markers. CD49f-high TICs specifically recruit tumor-promoting neutrophils via the CXCL2-CXCR2 axis and create an immunosuppressive milieu in the tumor microenvironment (TME). Reciprocally, the neutrophils reprogram nearby tumor cells toward a TIC phenotype via secreting CCL4. These cells can evade CD8+ T cell-mediated killing through CCL4/STAT3-induced and CD49f-stabilized CD155 expression. Notably, while aberrant CD155 expression contributes to immune suppression, it also represents a TIC-specific vulnerability. We demonstrate that either CD155 deletion or antibody blockade significantly enhances sensitivity to anti-PD-1 therapy in preclinical HCC models. Our findings reveal a new mechanism of tumor immune evasion and provide a rationale for combining CD155 blockade with anti-PD-1/PD-L1 therapy in HCC.
{"title":"Targeting the immune privilege of tumor-initiating cells to enhance cancer immunotherapy","authors":"Chen Yang, Haigang Geng, Xupeng Yang, Shuyi Ji, Zhicheng Liu, Hao Feng, Qian Li, Tangansu Zhang, Sisi Zhang, Xuhui Ma, Chuchen Zhu, Nuo Xu, Yuhan Xia, Yan Li, Hongye Wang, Chune Yu, Shangce Du, Beiping Miao, Lei Xu, Hui Wang, Cun Wang","doi":"10.1016/j.ccell.2024.10.008","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.008","url":null,"abstract":"Tumor-initiating cells (TICs) possess the ability to evade anti-tumor immunity, potentially explaining many failures of cancer immunotherapy. Here, we identify CD49f as a prominent marker for discerning TICs in hepatocellular carcinoma (HCC), outperforming other commonly used TIC markers. CD49f-high TICs specifically recruit tumor-promoting neutrophils via the CXCL2-CXCR2 axis and create an immunosuppressive milieu in the tumor microenvironment (TME). Reciprocally, the neutrophils reprogram nearby tumor cells toward a TIC phenotype via secreting CCL4. These cells can evade CD8<sup>+</sup> T cell-mediated killing through CCL4/STAT3-induced and CD49f-stabilized CD155 expression. Notably, while aberrant CD155 expression contributes to immune suppression, it also represents a TIC-specific vulnerability. We demonstrate that either CD155 deletion or antibody blockade significantly enhances sensitivity to anti-PD-1 therapy in preclinical HCC models. Our findings reveal a new mechanism of tumor immune evasion and provide a rationale for combining CD155 blockade with anti-PD-1/PD-L1 therapy in HCC.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"92 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07DOI: 10.1016/j.ccell.2024.10.010
Heng Lin, Kole Tison, Yuheng Du, Paul Kirchhoff, Chan Kim, Weichao Wang, Hannah Yang, Michael Pitter, Jiali Yu, Peng Liao, Jiajia Zhou, Linda Vatan, Sara Grove, Shuang Wei, Thomas Vigil, Yatrik M. Shah, Richard Mortensen, Ilona Kryczek, Lana Garmire, Jwala P. Sivaccumar, Weiping Zou
Immune checkpoint blockade (ICB) triggers tumor ferroptosis. However, most patients are unresponsive to ICB. Tumors might evade ferroptosis in the tumor microenvironment (TME). Here, we discover SLC13A3 is an itaconate transporter in tumor cells and endows tumor ferroptosis resistance, diminishing tumor immunity and ICB efficacy. Mechanistically, tumor cells uptake itaconate via SLC13A3 from tumor-associated macrophages (TAMs), thereby activating the NRF2-SLC7A11 pathway and escaping from immune-mediated ferroptosis. Structural modeling and molecular docking analysis identify a functional inhibitor for SLC13A3 (SLC13A3i). Deletion of ACOD1 (an essential enzyme for itaconate synthesis) in macrophages, genetic ablation of SLC13A3 in tumors, or treatment with SLC13A3i sensitize tumors to ferroptosis, curb tumor progression, and bolster ICB effectiveness. Thus, we identify the interplay between tumors and TAMs via the SLC13A3-itaconate-NRF2-SLC7A11 axis as a previously unknown immune ferroptosis resistant mechanism in the TME and SLC13A3 as a promising immunometabolic target for treating SLC13A3+ cancer.
{"title":"Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance","authors":"Heng Lin, Kole Tison, Yuheng Du, Paul Kirchhoff, Chan Kim, Weichao Wang, Hannah Yang, Michael Pitter, Jiali Yu, Peng Liao, Jiajia Zhou, Linda Vatan, Sara Grove, Shuang Wei, Thomas Vigil, Yatrik M. Shah, Richard Mortensen, Ilona Kryczek, Lana Garmire, Jwala P. Sivaccumar, Weiping Zou","doi":"10.1016/j.ccell.2024.10.010","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.010","url":null,"abstract":"Immune checkpoint blockade (ICB) triggers tumor ferroptosis. However, most patients are unresponsive to ICB. Tumors might evade ferroptosis in the tumor microenvironment (TME). Here, we discover SLC13A3 is an itaconate transporter in tumor cells and endows tumor ferroptosis resistance, diminishing tumor immunity and ICB efficacy. Mechanistically, tumor cells uptake itaconate via SLC13A3 from tumor-associated macrophages (TAMs), thereby activating the NRF2-SLC7A11 pathway and escaping from immune-mediated ferroptosis. Structural modeling and molecular docking analysis identify a functional inhibitor for SLC13A3 (SLC13A3i). Deletion of ACOD1 (an essential enzyme for itaconate synthesis) in macrophages, genetic ablation of SLC13A3 in tumors, or treatment with SLC13A3i sensitize tumors to ferroptosis, curb tumor progression, and bolster ICB effectiveness. Thus, we identify the interplay between tumors and TAMs via the SLC13A3-itaconate-NRF2-SLC7A11 axis as a previously unknown immune ferroptosis resistant mechanism in the TME and SLC13A3 as a promising immunometabolic target for treating SLC13A3<sup>+</sup> cancer.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"18 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594594","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 : 2024-10-31DOI: 10.1016/j.ccell.2024.10.001
James W. Smithy, Michael A. Postow
Combinatorial immunotherapy may improve the efficacy of neoadjuvant checkpoint inhibitors in locoregionally advanced melanoma. In this issue of Cancer Cell, Davar and colleagues report a promising phase 2 neoadjuvant trial of the TLR9 agonist vidutolimod in combination with nivolumab. Analyses suggest a unique myeloid expression signature is associated with response.
{"title":"Intratumoral vidutolimod in combination with PD-1 blockade in locoregionally advanced melanoma","authors":"James W. Smithy, Michael A. Postow","doi":"10.1016/j.ccell.2024.10.001","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.001","url":null,"abstract":"Combinatorial immunotherapy may improve the efficacy of neoadjuvant checkpoint inhibitors in locoregionally advanced melanoma. In this issue of <em>Cancer Cell</em>, Davar and colleagues report a promising phase 2 neoadjuvant trial of the TLR9 agonist vidutolimod in combination with nivolumab. Analyses suggest a unique myeloid expression signature is associated with response.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"32 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556311","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 : 2024-10-31DOI: 10.1016/j.ccell.2024.10.006
An ideal cell surface target has ubiquitously high cancer expression, absence from healthy tissues, and an essential role cancer initiation and/or mai…
{"title":"Targeting DLK1 in neuroblastoma","authors":"","doi":"10.1016/j.ccell.2024.10.006","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.006","url":null,"abstract":"An ideal cell surface target has ubiquitously high cancer expression, absence from healthy tissues, and an essential role cancer initiation and/or mai…","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"87 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556315","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 : 2024-10-31DOI: 10.1016/j.ccell.2024.10.007
Diwakar Davar, Robert M. Morrison, Amiran K. Dzutsev, Arivarasan Karunamurthy, Joe-Marc Chauvin, Florent Amatore, Julie S. Deutsch, Rodrigo X. Das Neves, Richard R. Rodrigues, John A. McCulloch, Hong Wang, Douglas J. Hartman, Jonathan H. Badger, Miriam R. Fernandes, Yulong Bai, Jie Sun, Alicia M. Cole, Poonam Aggarwal, Jennifer R. Fang, Christopher Deitrick, Hassane M. Zarour
Intratumoral TLR9 agonists and anti-PD-1 produce clinical responses and broad immune activation. We conducted a single-arm study of neoadjuvant TLR9 agonist vidutolimod combined with anti-PD-1 nivolumab in high-risk resectable melanoma. In 31 evaluable patients, 55% major pathologic response (MPR) was observed, meeting primary endpoint. MPR was associated with necrosis, and melanophagocytosis with increased CD8+ tumor-infiltrating lymphocytes and plasmacytoid dendritic cells (pDCs) in the tumor microenvironment, and increased frequencies of Ki67+CD8+ T cells peripherally. MPRs had an enriched pre-treatment gene signature of myeloid cells, and response to therapy was associated with gene signatures of immune cells, pDCs, phagocytosis, and macrophage activation. MPRs gut microbiota were enriched for Gram-negative bacteria belonging to the Bacteroidaceae and Enterobacteriaceae families and the small subgroup of Gram-negative Firmicutes. Our findings support that combined vidutolimod and nivolumab stimulates a broad anti-tumor immune response and is associated with distinct baseline myeloid gene signature and gut microbiota. ClinicalTrials.gov identifier: NCT03618641.
{"title":"Neoadjuvant vidutolimod and nivolumab in high-risk resectable melanoma: A prospective phase II trial","authors":"Diwakar Davar, Robert M. Morrison, Amiran K. Dzutsev, Arivarasan Karunamurthy, Joe-Marc Chauvin, Florent Amatore, Julie S. Deutsch, Rodrigo X. Das Neves, Richard R. Rodrigues, John A. McCulloch, Hong Wang, Douglas J. Hartman, Jonathan H. Badger, Miriam R. Fernandes, Yulong Bai, Jie Sun, Alicia M. Cole, Poonam Aggarwal, Jennifer R. Fang, Christopher Deitrick, Hassane M. Zarour","doi":"10.1016/j.ccell.2024.10.007","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.007","url":null,"abstract":"Intratumoral TLR9 agonists and anti-PD-1 produce clinical responses and broad immune activation. We conducted a single-arm study of neoadjuvant TLR9 agonist vidutolimod combined with anti-PD-1 nivolumab in high-risk resectable melanoma. In 31 evaluable patients, 55% major pathologic response (MPR) was observed, meeting primary endpoint. MPR was associated with necrosis, and melanophagocytosis with increased CD8<sup>+</sup> tumor-infiltrating lymphocytes and plasmacytoid dendritic cells (pDCs) in the tumor microenvironment, and increased frequencies of Ki67<sup>+</sup>CD8<sup>+</sup> T cells peripherally. MPRs had an enriched pre-treatment gene signature of myeloid cells, and response to therapy was associated with gene signatures of immune cells, pDCs, phagocytosis, and macrophage activation. MPRs gut microbiota were enriched for Gram-negative bacteria belonging to the Bacteroidaceae and Enterobacteriaceae families and the small subgroup of Gram-negative Firmicutes. Our findings support that combined vidutolimod and nivolumab stimulates a broad anti-tumor immune response and is associated with distinct baseline myeloid gene signature and gut microbiota. <span><span>ClinicalTrials.gov</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span> identifier: <span><span>NCT03618641</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"213 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556313","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 : 2024-10-31DOI: 10.1016/j.ccell.2024.10.005
Emily C. Harrold, Martinique Ogle, Erin O’Brien, Callahan Wilde, Jenna Sinopoli, Jill Weiss, Lauren Martino, Anne Casson, Hey-Joo Kang, Michael Postow, Andrea Cercek
Harrold et al. evaluate the fertility impact of checkpoint inhibitor blockade (ICB), demonstrating that unlike in utero exposure, post-exposure conception appears to result in uncomplicated pregnancies and healthy progeny. They demonstrate contemporaneous monitoring of temporal female hormonal fluctuations before, on, and post ICB exposure and prior to successful embryo implantation.
{"title":"Fertility outcomes post immune checkpoint inhibitor exposure","authors":"Emily C. Harrold, Martinique Ogle, Erin O’Brien, Callahan Wilde, Jenna Sinopoli, Jill Weiss, Lauren Martino, Anne Casson, Hey-Joo Kang, Michael Postow, Andrea Cercek","doi":"10.1016/j.ccell.2024.10.005","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.005","url":null,"abstract":"Harrold et al. evaluate the fertility impact of checkpoint inhibitor blockade (ICB), demonstrating that unlike <em>in utero</em> exposure, post-exposure conception appears to result in uncomplicated pregnancies and healthy progeny. They demonstrate contemporaneous monitoring of temporal female hormonal fluctuations before, on, and post ICB exposure and prior to successful embryo implantation.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"19 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556314","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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