Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity

被引：234

作者：

Hutton, Colin ^{[1
]}

Heider, Felix ^{[1
]}

Blanco-Gomez, Adrian ^{[1
]}

Banyard, Antonia ^{[2
]}

Kononov, Alexander ^{[1
]}

Zhang, Xiaohong ^{[1
]}

Karim, Saadia ^{[3
]}

Paulus-Hock, Viola ^{[3
]}

Watt, Dale ^{[3
]}

Steele, Nina ^{[4
,5
,6
]}

Kemp, Samantha ^{[5
,7
]}

Hogg, Elizabeth K. J. ^{[1
]}

Kelly, Joanna ^{[1
]}

Jackstadt, Rene-Filip ^{[3
]}

Lopes, Filipa ^{[8
]}

Menotti, Matteo ^{[9
]}

Chisholm, Luke ^{[10
]}

Lamarca, Angela ^{[11
]}

Valle, Juan ^{[11
,12
]}

Sansom, Owen J. ^{[3
,13
]}

Springer, Caroline ^{[8
]}

Malliri, Angeliki ^{[9
]}

Marais, Richard ^{[10
]}

di Magliano, Marina Pasca ^{[4
,5
]}

Zelenay, Santiago ^{[14
]}

Morton, Jennifer P. ^{[3
,13
]}

Jorgensen, Claus ^{[1
]}

机构：

[1] Canc Res UK Manchester Inst, Syst Oncol, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England

[2] Canc Res UK Manchester Inst, Flow Cytometry Core, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England

[3] Canc Res UK Beatson Inst, Garscube Estate, Glasgow G61 1BD, Lanark, Scotland

[4] Univ Michigan, Rogel Canc Ctr, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA

[6] Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA

[7] Univ Michigan, Mol & Cellular Pathol Grad Program, Ann Arbor, MI 48109 USA

[8] Canc Res UK Manchester Inst, Drug Discovery Unit, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England

[9] Canc Res UK Manchester Inst, Cell Signalling, Alderley Pk, Manchester SK10 4TG, Lancs, England

[10] Canc Res UK Manchester Inst, Mol Oncol, Alderley Pk, Manchester SK10 4TG, Lancs, England

[11] Christie NHS Fdn Trust, Dept Med Oncol, Wilmslow Rd, Manchester M20 4BX, Lancs, England

[12] Univ Manchester, Inst Canc Sci, Wilmslow Rd, Manchester M20 4BX, Lancs, England

[13] Univ Glasgow, Inst Canc Sci, Switchback Rd,Garscube Estate, Glasgow G61 1QH, Lanark, Scotland

[14] Canc Res UK Manchester Inst, Canc Immun & Inflammat, Alderley Pk, Manchester SK10 4TG, Lancs, England

来源：

CANCER CELL | 2021年 / 39卷 / 09期

基金：

欧洲研究理事会;

关键词：

SMOOTH-MUSCLE-CELLS; MOUSE MODEL; CANCER; INHIBITION; EXPRESSION; MICE; REVEALS; IMMUNOTHERAPY; HETEROGENEITY; MESOTHELIUM;

D O I：

10.1016/j.ccell.2021.06.017

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Fibroblasts display extensive transcriptional heterogeneity, yet functional annotation and characterization of their heterocellular relationships remains incomplete. Using mass cytometry, we chart the stromal composition of 18 murine tissues and 5 spontaneous tumor models, with an emphasis on mesenchymal phenotypes. This analysis reveals extensive stromal heterogeneity across tissues and tumors, and identifies coordinated relationships between mesenchymal and immune cell subsets in pancreatic ductal adenocarcinoma. Expression of CD105 demarks two stable and functionally distinct pancreatic fibroblast lineages, which are also identified in murine and human healthy tissues and tumors. Whereas CD105-positive pancreatic fibroblasts are permissive for tumor growth in vivo, CD105-negative fibroblasts are highly tumor suppressive. This restrictive effect is entirely dependent on functional adaptive immunity. Collectively, these results reveal two functionally distinct pancreatic fibroblast lineages and highlight the importance of mesenchymal and immune cell interactions in restricting tumor growth.

引用

页码：1227 / +

页数：38

共 91 条

[1]

Anders S., 2010, GENOME BIOL, V11, pR106, DOI [10.1186/gb-2010-11-10-r106, DOI 10.1186/gb-2010-11-10-r106]

[2] QuPath: Open source software for digital pathology image analysis [J].

Bankhead, Peter ;

Loughrey, Maurice B. ;

Fernandez, Jose A. ;

Dombrowski, Yvonne ;

Mcart, Darragh G. ;

Dunne, Philip D. ;

McQuaid, Stephen ;

Gray, Ronan T. ;

Murray, Liam J. ;

Coleman, Helen G. ;

James, Jacqueline A. ;

Salto-Tellez, Manuel ;

Hamilton, Peter W. .

SCIENTIFIC REPORTS, 2017, 7

[3] Dimensionality reduction for visualizing single-cell data using UMAP [J].

Becht, Etienne ;

McInnes, Leland ;

Healy, John ;

Dutertre, Charles-Antoine ;

Kwok, Immanuel W. H. ;

Ng, Lai Guan ;

Ginhoux, Florent ;

Newell, Evan W. .

NATURE BIOTECHNOLOGY, 2019, 37 (01) :38-+

[4] Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression [J].

Becht, Etienne ;

Giraldo, Nicolas A. ;

Lacroix, Laetitia ;

Buttard, Benedicte ;

Elarouci, Nabila ;

Petitprez, Florent ;

Selves, Janick ;

Laurent-Puig, Pierre ;

Sautes-Fridman, Catherine ;

Fridman, Wolf H. ;

de Reynies, Aurelien .

GENOME BIOLOGY, 2016, 17

[5] From single cells to deep phenotypes in cancer [J].

Bendall, Sean C. ;

Nolan, Garry P. .

NATURE BIOTECHNOLOGY, 2012, 30 (07) :639-647

[6] Single-Cell Mass Cytometry of Differential Immune and Drug Responses Across a Human Hematopoietic Continuum [J].

Bendall, Sean C. ;

Simonds, Erin F. ;

Qiu, Peng ;

Amir, El-ad D. ;

Krutzik, Peter O. ;

Finck, Rachel ;

Bruggner, Robert V. ;

Melamed, Rachel ;

Trejo, Angelica ;

Ornatsky, Olga I. ;

Balderas, Robert S. ;

Plevritis, Sylvia K. ;

Sachs, Karen ;

Pe'er, Dana ;

Tanner, Scott D. ;

Nolan, Garry P. .

SCIENCE, 2011, 332 (6030) :687-696

[7] IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma [J].

Biffi, Giulia ;

Oni, Tobiloba E. ;

Spielman, Benjamin ;

Hao, Yuan ;

Elyada, Ela ;

Park, Youngkyu ;

Preall, Jonathan ;

Tuveson, David A. .

CANCER DISCOVERY, 2019, 9 (02) :282-301

[8] Integrating single-cell transcriptomic data across different conditions, technologies, and species [J].

Butler, Andrew ;

Hoffman, Paul ;

Smibert, Peter ;

Papalexi, Efthymia ;

Satija, Rahul .

NATURE BIOTECHNOLOGY, 2018, 36 (05) :411-+

[9] CSF1R+ Macrophages Sustain Pancreatic Tumor Growth through T Cell Suppression and Maintenance of Key Gene Programs that Define the Squamous Subtype [J].

Candido, Juliana B. ;

Morton, Jennifer P. ;

Bailey, Peter ;

Campbell, Andrew D. ;

Karim, Saadia A. ;

Jamieson, Thomas ;

Lapienyte, Laura ;

Gopinathan, Aarthi ;

Clark, William ;

McGhee, Ewan J. ;

Wang, Jun ;

Escorcio-Correia, Monica ;

Zollinger, Raphael ;

Roshani, Rozita ;

Drew, Lisa ;

Rishi, Loveena ;

Arkell, Rebecca ;

Evans, T. R. Jeffry ;

Nixon, Colin ;

Jodrell, Duncan I. ;

Wilkinson, Robert W. ;

Biankin, Andrew V. ;

Barry, Simon T. ;

Balkwill, Frances R. ;

Sansom, Owen J. .

CELL REPORTS, 2018, 23 (05) :1448-1460

[10] Wt1-expressing progenitors contribute to multiple tissues in the developing lung [J].

Cano, Elena ;

Carmona, Rita ;

Munoz-Chapuli, Ramon .

AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2013, 305 (04) :L322-L332

← 1 2 3 4 5 6 7 8 9 10 →