Single-cell RNA sequencing reveals evolution of immune landscape during glioblastoma progression

被引：173

作者：

Yeo, Alan T. ^{[1
,2
]}

Rawal, Shruti ^{[1
]}

Delcuze, Bethany ^{[1
,2
]}

Christofides, Anthos ^{[1
]}

Atayde, Agata ^{[1
]}

Strauss, Laura ^{[1
]}

Balaj, Leonora ^{[3
]}

Rogers, Vaughn A. ^{[1
]}

Uhlmann, Erik J. ^{[4
]}

Varma, Hemant ^{[5
]}

Carter, Bob S. ^{[3
]}

Boussiotis, Vassiliki A. ^{[1
,6
]}

Charest, Al ^{[1
,6
]}

机构：

[1] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA

[2] Tufts Univ, Sch Med, Sackler Sch Grad Studies, Boston, MA 02111 USA

[3] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02115 USA

[4] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02115 USA

[5] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02115 USA

[6] Beth Israel Deaconess Med Ctr, Canc Res Inst, Boston, MA 02215 USA

来源：

NATURE IMMUNOLOGY | 2022年 / 23卷 / 06期

基金：

美国国家卫生研究院;

关键词：

PERIVASCULAR MACROPHAGES; SUPPRESSOR-CELLS; CROSS-TALK; EXPRESSION; MOUSE; RECEPTOR; IMMUNOTHERAPY; PROLIFERATION; ANGIOGENESIS; TEMOZOLOMIDE;

D O I：

10.1038/s41590-022-01215-0

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Glioblastoma (GBM) is an incurable primary malignant brain cancer hallmarked with a substantial protumorigenic immune component. Knowledge of the GBM immune microenvironment during tumor evolution and standard of care treatments is limited. Using single-cell transcriptomics and flow cytometry, we unveiled large-scale comprehensive longitudinal changes in immune cell composition throughout tumor progression in an epidermal growth factor receptor-driven genetic mouse GBM model. We identified subsets of proinflammatory microglia in developing GBMs and anti-inflammatory macrophages and protumorigenic myeloid-derived suppressors cells in end-stage tumors, an evolution that parallels breakdown of the blood-brain barrier and extensive growth of epidermal growth factor receptor(+) GBM cells. A similar relationship was found between microglia and macrophages in patient biopsies of low-grade glioma and GBM. Temozolomide decreased the accumulation of myeloid-derived suppressor cells, whereas concomitant temozolomide irradiation increased intratumoral GranzymeB(+) CD8(+)T cells but also increased CD4(+) regulatory T cells. These results provide a comprehensive and unbiased immune cellular landscape and its evolutionary changes during GBM progression. Single-cell RNAseq during initiation and progression of mouse glioblastoma reveals a dynamic immune microenvironment transitioning from pro-inflammatory microglia in early tumors towards an infiltrating macrophage and suppressor cell-centric immune landscape in late-stage tumors.

引用

页码：971 / +

页数：38

共 79 条

[1] Chronic Activation of Wild-Type Epidermal Growth Factor Receptor and Loss of Cdkn2a Cause Mouse Glioblastoma Formation [J].

Acquaviva, Jaime ;

Jun, Hyun Jung ;

Lessard, Julie ;

Ruiz, Rolando ;

Zhu, Haihao ;

Donovan, Melissa ;

Woolfenden, Steve ;

Boskovitz, Abraham ;

Raval, Ami ;

Bronson, Roderick T. ;

Pfannl, Rolf ;

Whittaker, Charles A. ;

Housman, David E. ;

Al Charest .

CANCER RESEARCH, 2011, 71 (23) :7198-7206

[2] xCell: digitally portraying the tissue cellular heterogeneity landscape [J].

Aran, Dvir ;

Hu, Zicheng ;

Butte, Atul J. .

GENOME BIOLOGY, 2017, 18

[3] T-cell defect in diffuse large B-cell lymphomas involves expansion of myeloid-derived suppressor cells [J].

Azzaoui, Imane ;

Uhel, Fabrice ;

Rossille, Delphine ;

Pangault, Celine ;

Dulong, Joelle ;

Le Priol, Jerome ;

Lamy, Thierry ;

Houot, Roch ;

Le Gouill, Steven ;

Cartron, Guillaume ;

Godmer, Pascal ;

Bouabdallah, Krimo ;

Milpied, Noel ;

Damaj, Gandhi ;

Tarte, Karin ;

Fest, Thierry ;

Roussel, Mikael .

BLOOD, 2016, 128 (08) :1081-1092

[4] scds: computational annotation of doublets in single-cell RNA sequencing data [J].

Bais, Abha S. ;

Kostka, Dennis .

BIOINFORMATICS, 2020, 36 (04) :1150-1158

[5] Expression of CXC chemokine receptors 1-5 and their ligands in human glioma tissues: Role of CXCR4 and SDF1 in glioma cell proliferation and migration [J].

Bajetto, Adriana ;

Barbieri, Federica ;

Dorcaratto, Alessandra ;

Barbero, Simone ;

Daga, Antonio ;

Porcile, Carola ;

Ravetti, Jean Louis ;

Zona, Gianluigi ;

Spaziante, Renato ;

Corte, Giorgio ;

Schettini, Gennaro ;

Florio, Tullio .

NEUROCHEMISTRY INTERNATIONAL, 2006, 49 (05) :423-432

[6] New tools for studying microglia in the mouse and human CNS [J].

Bennett, Mariko L. ;

Bennett, F. Chris ;

Liddelow, Shane A. ;

Ajami, Bahareh ;

Zamanian, Jennifer L. ;

Fernhoff, Nathaniel B. ;

Mulinyawe, Sara B. ;

Bohlen, Christopher J. ;

Adil, Aykezar ;

Tucker, Andrew ;

Weissman, Irving L. ;

Chang, Edward F. ;

Li, Gordon ;

Grant, Gerald A. ;

Gephart, Melanie G. Hayden ;

Barres, Ben A. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2016, 113 (12) :E1738-E1746

[7] Immunotherapies for malignant glioma [J].

Boussiotis, Vassiliki A. ;

Charest, Alain .

ONCOGENE, 2018, 37 (09) :1121-1141

[8] Macrophage Ontogeny Underlies Differences in Tumor-Specific Education in Brain Malignancies [J].

Bowman, Robert L. ;

Klemm, Florian ;

Akkari, Leila ;

Pyonteck, Stephanie M. ;

Sevenich, Lisa ;

Quail, Daniela F. ;

Dhara, Surajit ;

Simpson, Kenishana ;

Gardner, Eric E. ;

Iacobuzio-Donahue, Christine A. ;

Brennan, Cameron W. ;

Tabar, Viviane ;

Gutin, Philip H. ;

Joyce, Johanna A. .

CELL REPORTS, 2016, 17 (09) :2445-2459

[9] Near-optimal probabilistic RNA-seq quantification (vol 34, pg 525, 2016) [J].

Bray, Nicolas L. ;

Pimentel, Harold ;

Melsted, Pall ;

Pachter, Lior .

NATURE BIOTECHNOLOGY, 2016, 34 (08) :888-888

[10] The Somatic Genomic Landscape of Glioblastoma [J].

Brennan, Cameron W. ;

Verhaak, Roel G. W. ;

McKenna, Aaron ;

Campos, Benito ;

Noushmehr, Houtan ;

Salama, Sofie R. ;

Zheng, Siyuan ;

Chakravarty, Debyani ;

Sanborn, J. Zachary ;

Berman, Samuel H. ;

Beroukhim, Rameen ;

Bernard, Brady ;

Wu, Chang-Jiun ;

Genovese, Giannicola ;

Shmulevich, Ilya ;

Barnholtz-Sloan, Jill ;

Zou, Lihua ;

Vegesna, Rahulsimham ;

Shukla, Sachet A. ;

Ciriello, Giovanni ;

Yung, W. K. ;

Zhang, Wei ;

Sougnez, Carrie ;

Mikkelsen, Tom ;

Aldape, Kenneth ;

Bigner, Darell D. ;

Van Meir, Erwin G. ;

Prados, Michael ;

Sloan, Andrew ;

Black, Keith L. ;

Eschbacher, Jennifer ;

Finocchiaro, Gaetano ;

Friedman, William ;

Andrews, David W. ;

Guha, Abhijit ;

Iacocca, Mary ;

O'Neill, Brian P. ;

Foltz, Greg ;

Myers, Jerome ;

Weisenberger, Daniel J. ;

Penny, Robert ;

Kucherlapati, Raju ;

Perou, Charles M. ;

Hayes, D. Neil ;

Gibbs, Richard ;

Marra, Marco ;

Mills, Gordon B. ;

Lander, Eric ;

Spellman, Paul ;

Wilson, Richard .

CELL, 2013, 155 (02) :462-477

← 1 2 3 4 5 6 7 8 →