Open AccessSpatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images
Author(s) -
Joel Saltz,
Rajarsi Gupta,
Le Hou,
Tahsin Kurç,
Pankaj K. Singh,
Vu Nguyen,
Dimitris Samaras,
Kenneth R. Shroyer,
Tianhao Zhao,
Rebecca Batiste,
John Van Arnam,
Ilya Shmulevich,
Arvind Rao,
Alexander J. Lazar,
Ashish Sharma,
Vésteinn Thórsson,
Rory Johnson,
John A. Demchok,
Ina Felau,
Melpomeni Kasapi,
Martin L. Ferguson,
Carolyn M. Hutter,
Heidi J. Sofia,
Roy Tarnuzzer,
Linghua Wang,
Liming Yang,
Jean C. Zenklusen,
Jiashan Zhang,
Sudha Chudamani,
Jia Liu,
Laxmi Lolla,
Rashi Naresh,
Todd Pihl,
Qiang Sun,
Yunhu Wan,
Ye Wu,
Juok Cho,
Timothy Defreitas,
Scott Frazer,
Nils Gehlenborg,
Gad Getz,
David I. Heiman,
Seungchan Kim,
Michael S. Lawrence,
Pei Lin,
Thomas J. Giordano,
Michael S. Noble,
Gordon Saksena,
Doug Voet,
Hailei Zhang,
Brady Bernard,
Nyasha Chambwe,
Varsha Dhankani,
Theo Knijnenburg,
Roger Kramer,
Kalle Lein,
Yuexin Liu,
Michael Miller,
Sheila M. Reynolds,
Wei Zhang,
Rehan Akbani,
Bradley M. Broom,
Apurva M. Hegde,
Zhenlin Ju,
Rupa S. Kanchi,
Anil Korkut,
Jun Li,
Han Liang,
Shiyun Ling,
Wenbin Liu,
Yiling Lu,
Gordon B. Mills,
Patrick KwokShing Ng,
Michael P. Ryan,
Jing Wang,
John N. Weinstein,
Jiexin Zhang,
Adam Abeshouse,
Joshua Armenia,
Debyani Chakravarty,
Walid K. Chatila,
Ino de Bruijn,
Galen F. Gao,
Benjamin Groß,
Zachary Heins,
Ritika Kundra,
Konnor La,
Marc Ladanyi,
Augustin Luna,
Moriah G. Nissan,
Angelica Ochoa,
Sarah Phillips,
Ed Reznik,
Francisco Sánchez-Vega,
Chris Sander,
Nikolaus Schultz,
Robert E. Sheridan,
S. Onur Sumer,
Yichao Sun,
Barry S. Taylor,
Jioajiao Wang,
Hongxin Zhang,
Pavana Anur,
Myron Peto,
Paul T. Spellman,
Christopher C. Benz,
Joshua M. Stuart,
Christopher K. Wong,
Christina Yau,
D. Neil Hayes,
Joel S. Parker,
Matthew D. Wilkerson,
Adrian Ally,
Miruna Balasundaram,
Reanne Bowlby,
Denise Brooks,
Rebecca Carlsen,
Eric Chuah,
Noreen Dhalla,
Robert A. Holt,
Steven J.M. Jones,
L. Sylvia,
Darlene Lee,
Yussanne Ma,
Marco A. Marra,
Michael Mayo,
Richard A. Moore,
Andrew J. Mungall,
Karen Mungall,
A. Gordon Robertson,
Sara Sadeghi,
Jacqueline E. Schein,
Payal Sipahimalani,
Angela Tam,
Nina Thiessen,
Kane Tse,
Tina Wong,
Ashton C. Berger,
Rameen Beroukhim,
Andrew D. Cherniack,
Carrie Cibulskis,
Stacey Gabriel,
Gavin Ha,
Matthew Meyerson,
Steven E. Schumacher,
Juliann Shih,
Melanie H. Kucherlapati,
Raju Kucherlapati,
Stephen B. Baylin,
Leslie Cope,
Ludmila Danilova,
Arnoud Boot,
Phillip H. Lai,
Dennis T. Maglinte,
David Van Den Berg,
Daniel J. Weisenberger,
J. Todd Auman,
Saianand Balu,
Tom Bodenheimer,
Huihui Fan,
Katherine A. Hoadley,
Alan P. Hoyle,
Corbin D. Jones,
Shaowu Meng,
Piotr A. Mieczkowski,
Lisle E. Mose,
Amy H. Perou,
Charles M. Perou,
Jeffrey Roach,
Yan Shi,
Janae V. Simons,
Tara Skelly,
Matthew G. Soloway,
Donghui Tan,
Umadevi Veluvolu,
Toshinori Hinoue,
Peter W. Laird,
Hui Shen,
Wanding Zhou,
Michelle Bellair,
Kyle Chang,
Kyle R. Covington,
Chad J. Creighton,
Huyen Dinh,
HarshaVardhan Doddapaneni,
Lawrence A. Donehower,
Jennifer Drummond,
Richard A. Gibbs,
Robert Glenn,
Walker Hale,
Yi Han,
Hai Hu,
Viktoriya Korchina,
Charles Lee,
Lora Lewis,
Wei Li,
Xiuping Liu,
Margaret Morgan,
Donna Morton,
Donna M. Muzny,
Jireh Santibanez,
Margi Sheth,
Eve Shinbrot,
Min Wang,
David A. Wheeler,
Liu Xi,
Fengmei Zhao,
Julian M. Hess,
Elizabeth L. Appelbaum,
Matthew H. Bailey,
Matthew G. Cordes,
Li Ding,
Catrina C. Fronick,
Lucinda A. Fulton,
Robert S. Fulton,
Cyriac Kandoth,
Elaine R. Mardis,
Michael D. McLellan,
Christopher A. Miller,
Heather K. Schmidt,
Richard K. Wilson,
Daniel Crain,
Erin Curley,
Johanna Gardner,
Kevin Lau,
David Mallery,
Scott Morris,
Joseph Paulauskis,
Robert Penny,
Candace Shelton,
Troy Shelton,
Mark E. Sherman,
Eric Thompson,
Peggy Yena,
Jay Bowen,
Julie M. Gastier-Foster,
Mark Gerken,
Kristen M. Leraas,
Tara M. Lichtenberg,
Nilsa C. Ramirez,
Lisa Wise,
Erik Zmuda,
Niall M. Corcoran,
Tony Costello,
Christopher M. Hovens,
André Lopes Carvalho,
Ana Carolina de Carvalho,
José Humberto Tavares Guerreiro Fregnani,
Adhemar LongattoFilho,
Rui Manuel Reis,
Cristovam ScapulatempoNeto,
Henrique C.S. Silveira,
Daniel Onofre Vidal,
Andrew Burnette,
Jennifer Eschbacher,
Beth Hermes,
Ardene Noss,
Rosy Singh,
Matthew L. Anderson,
Patricia D. Castro,
Michael Ittmann,
David Huntsman,
Bernard Kohl,
Xuan Le,
Richard Thorp,
Chris Andry,
Elizabeth R. Duffy,
Vladimir Lyadov,
Oxana Paklina,
Galiya Setdikova,
Shabunin Av,
Mikhail Tavobilov,
Christopher McPherson,
Ronald E. Warnick,
Ross S. Berkowitz,
Daniel W. Cramer,
Colleen M. Feltmate,
Neil S. Horowitz,
Adam S. Kibel,
Michael G. Muto,
Chandrajit P. Raut,
Andrei Malykh,
Jill S. BarnholtzSloan,
Wendi Barrett,
Karen Devine,
Jordonna Fulop,
Quinn T. Ostrom,
Kristen Shimmel,
Yingli Wolinsky,
Andrew E. Sloan,
Agostino Maria De Rose,
Felice Giuliante,
Marc T. Goodman,
Beth Y. Karlan,
Curt H. Hagedorn,
John Eckman,
Jodi Harr,
Jerome K. Myers,
Kelinda Tucker,
Leigh Anne Zach,
Brenda Deyarmin,
Leonid Kvecher,
Caroline Larson,
Richard Mural,
Stella Somiari,
Aleš Vícha,
Tomáš Zelinka,
Joseph Bennett,
Mary Iacocca,
Brenda Rabeno,
Patricia Swanson,
Mathieu Latour,
Louis Lacombe,
Bernard Têtu,
Alain Bergeron,
Mary McGraw,
Susan M. Staugaitis,
John A. Chabot,
Hanina Hibshoosh,
Antonia R. Sepulveda,
Tao Su,
Timothy C. Wang,
Olga Potapova,
О. Л. Воронина,
Laurence Desjardins,
Odette Mariani,
Sergio Román-Román,
Xavier Sastre,
MarcHenri Stern,
Feixiong Cheng,
Sabina Signoretti,
Andrew Berchuck,
Darell D. Bigner,
Eric Lipp,
Jeffrey S. Marks,
Shan J. McCall,
Roger E. McLendon,
Angeles Alvarez Secord,
Alexis Sharp,
Madhusmita Behera,
Daniel J. Brat,
Amy Chen,
Keith A. Delman,
Seth Force,
Fadlo R. Khuri,
Kelly R. Magliocca,
Shishir K. Maithel,
Jeffrey J. Olson,
Taofeek K. Owonikoko,
Alan Pickens,
Suresh S. Ramalingam,
Dong M. Shin,
Gabriel Sica,
Erwin G. Van Meir,
Hongzheng Zhang,
Wil Eijckenboom,
Ad Gillis,
Esther Korpershoek,
Leendert H. J. Looijenga,
Wolter Oosterhuis,
Hans Stoop,
Kim E. van Kessel,
Ellen C. Zwarthoff,
Chiara Calatozzolo,
Lucia Cuppini,
Stefania Cuzzubbo,
Francesco DiMeco,
Gaetano Finocchiaro,
Luca Mattei,
Alessandro Perin,
Bianca Pollo,
Chen Chu,
J. C. Houck,
Pawadee Lohavanichbutr,
Arndt Hartmann,
Robert Stoehr,
Helge Täubert,
Sven Wach,
Bernd Wullich,
Witold Kycler,
Dawid Murawa,
Maciej Wiznerowicz,
Ki Y. Chung,
W. Jeffrey Edenfield,
Julie Martin,
Éric Baudin,
Glenn J. Bubley,
Raphael Bueno,
Assunta De Rienzo,
William G. Richards,
Steven N. Kalkanis,
Tom Mikkelsen,
Houtan Noushmehr,
Lisa Scarpace,
Nicolas Girard,
Marta Aymerich,
Elı́as Campo,
Eva Giné,
Armando López Guillermo,
Nguyen Van Bang,
Phan Thi Hanh,
Bùi Đức Phú,
Yufang Tang,
Howard Colman,
Kimberley Evason,
Peter R. Dottino,
John A. Martignetti,
Hani Gabra,
Hartmut Juhl,
Teniola Akeredolu,
Serghei Stepa,
Dave S.�B. Hoon,
Keunsoo Ahn,
Koo Jeong Kang,
Felix Beuschlein,
Anne Breggia,
Michael J. Birrer,
Debra Bell,
Mitesh J. Borad,
Alan H. Bryce,
Erik P. Castle,
Vishal S. Chandan,
John C. Cheville,
John A. Copland,
Michael B. Farnell,
Thomas J. Flotte,
Nasra H. Giama,
Thai H. Ho,
Michael L. Kendrick,
JeanPierre Kocher,
Karla Kopp,
Catherine D. Moser,
David M. Nagorney,
Daniel J. O’Brien,
Brian Patrick O’Neill,
Tushar Patel,
Gloria Petersen,
Florencia G. Que,
Michael Rivera,
Lewis R. Roberts,
Robert C. Smallridge,
Thomas C. Smyrk,
Melissa Stanton,
R. Houston Thompson,
Michael Torbenson,
Ju Dong Yang,
Lizhi Zhang,
Fadi Brimo,
Jaffer A. Ajani,
Ana Maria Angulo Gonzalez,
Carmen Behrens,
Jolanta Bondaruk,
Russell R. Broaddus,
Bogdan Czerniak,
Bita Esmaeli,
Junya Fujimoto,
Charles Guo,
Christopher J. Logothetis,
Funda MericBernstam,
César A. Moran,
Lois M. Ramondetta,
David C. Rice,
Anil K. Sood,
Pheroze Tamboli,
Timothy C. Thompson,
Patricia Troncoso,
Anne S. Tsao,
Ignacio Wistuba,
Candace Carter,
Lauren E. Haydu,
Peter Hersey,
Valerie Jakrot,
Hojabr Kakavand,
Richard Kefford,
Kenneth Lee,
Georgina V. Long,
Graham J. Mann,
Michael C. Quinn,
Robyn P.M. Saw,
Richard A. Scolyer,
Kerwin F. Shan,
Andrew J. Spillane,
onathan Stretch,
Maria Synott,
John Thompson,
James S. Wilmott,
Hikmat AlAhmadie,
Timothy A. Chan,
Ronald Ghossein,
Anuradha Gopalan,
Douglas A. Levine,
Victor Reuter,
Samuel Singer,
Bhuvanesh Singh,
Nguyen Viet Tien,
Thomas Broudy,
Cyrus Mirsaidi,
Praveen Nair,
Paul Drwiega,
Judy Miller,
Jennifer A. Smith,
Howard Zaren,
Joong-Won Park,
Nguyễn Phi Hùng,
Electron Kebebew,
W. Marston Linehan,
Adam R. Metwalli,
Karel Pacák,
Peter A. Pinto,
Mark Schiffman,
Laura S. Schmidt,
Cathy D. Vocke,
Nicolas Wentzensen,
Robert Worrell,
Hannah Yang,
Marc Moncrieff,
Chandra Goparaju,
Jonathan Melamed,
Harvey I. Pass,
Natalia Botnariuc,
Irina Caraman,
Mircea Cernat,
Inga Chemencedji,
Adrian Clipca,
Serghei Doruc,
Ghenadie Gorincioi,
Sergiu Mura,
Maria Pirtac,
Irina Stancul,
Diana Tcaciuc,
Monique Albert,
Iakovina Alexopoulou,
Angel Arnaout,
John Bartlett,
Jay Engel,
Sebastién Gilbert,
Jeremy Parfitt,
Harman Sekhon,
George Thomas,
Doris M. Rassl,
Robert C. Rintoul,
Carlo Bifulco,
Raina Tamakawa,
Walter J. Urba,
Nicholas K. Hayward,
Henri Timmers,
Anna Antenucci,
Francesco Facciolo,
Gian Luca Grazi,
Mirella Marino,
Roberta Merola,
Ronald R. de Krijger,
AnnePaule GimenezRoqueplo,
Alain Piché,
Simone Chevalier,
Ginette McKercher,
Kıvanç Birsoy,
Gene H. Barnett,
Cathy Brewer,
Carol Farver,
Theresa Naska,
Nathan A. Pennell,
Daniel Raymond,
Cathy Schilero,
Kathy Smolenski,
Cecilia Williams,
Quaid Morris,
Jeffrey A. Borgia,
Mark Pool,
Christopher W. Seder,
Kerstin Junker,
Larsson Omberg,
Mikhail Dinkin,
George Manikhas,
Domenico Alvaro,
Maria Consiglia Bragazzi,
Vincenzo Cardinale,
Guido Carpino,
Eugenio Gaudio,
David Chesla,
Sandra Cottingham,
Michael Dubina,
Fedor Moiseenko,
Renumathy Dhanasekaran,
KarlFriedrich Becker,
Klaus–Peter Janssen,
Julia SlottaHuspenina,
Mohamed H. AbdelRahman,
Dina Aziz,
Sue Bell,
Colleen M. Cebulla,
Amy Davis,
Rebecca Duell,
J. Bradley Elder,
Joe Hilty,
Bahavna Kumar,
James C. Lang,
Norman L. Lehman,
Randy Mandt,
Phuong Nguyen,
Robert Pilarski,
Karan Rai,
Lynn Schoenfield,
Kelly Senecal,
Paul E. Wakely,
Paul Hansen,
Ronald M. Lechan,
James F. Powers,
Arthur S. Tischler,
William E. Grizzle,
Katherine C. Sexton,
Alison Kastl,
Joel Henderson,
Sima P. Porten,
Jens Waldmann,
Martin Faßnacht,
Dirk Schadendorf,
Marta Couce,
Markus Graefen,
Hartwig Huland,
Guido Sauter,
Thorsten Schlomm,
Ronald Simon,
Pierre Tennstedt,
Oluwole Olabode,
Mark A. Nelson,
Oliver F. Bathe,
Peter R. Carroll,
June M. Chan,
Philip J. DiSaia,
Pat Glenn,
Robin Kate Kelley,
Charles N. Landen,
Joanna Phillips,
Michael Prados,
Jeffry Simko,
Karen SmithMcCune,
Scott Vandenberg,
Kevin K. Roggin,
Ashley Fehrenbach,
Ady Kendler,
Suzanne Sifri,
Ruth Steele,
Antonio Jimeno,
Francis A. Carey,
Ian Forgie,
Massimo Mannelli,
Michael E. Carney,
Brenda Hernandez,
Benito Campos,
Christel HeroldMende,
Christin Jungk,
Andreas Unterberg,
Andreas von Deimling,
Aaron Bossler,
Joseph Galbraith,
Laura Jacobus,
Michael Knudson,
Tina Knutson,
Deqin Ma,
Mohammed Milhem,
Rita Sigmund,
Andrew K. Godwin,
Rashna Madan,
Howard G. Rosenthal,
Clement Adebamowo,
Sally N. Adebamowo,
Alex Boussioutas,
David G. Beer,
AnneMarie MesMasson,
Fred Saad,
Thèrése Bocklage,
Lisa M. Landrum,
Robert S. Mannel,
Kathleen N. Moore,
Katherine Moxley,
Russel Postier,
Joan Walker,
Rosemary E. Zuna,
Michael D. Feldman,
Federico Valdivieso,
Rajiv Dhir,
James D. Luketich,
Edna M. Mora Pinero,
Mario Quintero-Aguilo,
Carlos Gilberto Carlotti,
José Sebastião dos Santos,
Rafael Kemp,
Ajith Sankarankuty,
Daniela Tirapelli,
James W.F. Catto,
Kathy Agnew,
Elizabeth M. Swisher,
Jenette Creaney,
Bruce Robinson,
Carl Simon Shelley,
Eryn M. Godwin,
Sara Kendall,
Cassaundra Shipman,
Carol R. Bradford,
Thomas E. Carey,
Robert I. Haddad,
Jeffey Moyer,
Lisa A. Peterson,
Mark E. Prince,
Laura S. Rozek,
Gregory T. Wolf,
Rayleen Bowman,
Kwun M. Fong,
Ian A. Yang,
Robert J. Korst,
W. Kimryn Rathmell,
J. Leigh Fantacone-Campbell,
Jeffrey A. Hooke,
Albert J. Kovatich,
Craig D. Shriver,
John F. DiPersio,
Bettina F. Drake,
Ramaswamy Govindan,
Sharon E. Heath,
Timothy J. Ley,
Brian A. Van Tine,
Peter Westervelt,
Mark A. Rubin,
Jung Il Lee,
Natália D. Aredes,
Armaz Mariamidze
Publication year - 2018
Publication title -
cell reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.264
H-Index - 154
eISSN - 2639-1856
pISSN - 2211-1247
DOI - 10.1016/j.celrep.2018.03.086
Subject(s) - convolutional neural network , tumor infiltrating lymphocytes , biology , immunohistochemistry , correlation , pathology , tumor microenvironment , computational biology , spatial analysis , digital pathology , immune system , artificial intelligence , immunotherapy , computer science , immunology , medicine , mathematics , geometry , statistics
Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumor-infiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment.
Accelerating Research
Robert Robinson Avenue,
Oxford Science Park, Oxford
OX4 4GP, United Kingdom
Address
John Eccles HouseRobert Robinson Avenue,
Oxford Science Park, Oxford
OX4 4GP, United Kingdom