Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

作者：Joel Haskin Saltz, Rajarsi Gupta, Le Hou, Tahsin Kurç, Pankaj Kumar Singh, Vu Nguyen, Dimitris Samaras, Kenneth R. Shroyer, Tianhao Zhao, Rebecca Batiste, John Van Arnam, Rory Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy W Tarnuzzer, Zhining Wang, Liming Yang, Jean Claude 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 A. Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Yi Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady M. Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Yuexin Liu, Michael Miller, Sheila M. Reynolds, Ilya Shmulevich, Vésteinn Thórsson, Vésteinn Thorsson, Wei Zhang, Rehan Akbani, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Han Liang, Shiyun Ling, Shiyun Ling, Yiling Lu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, John N. Weinstein, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Marc Ladanyi, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sánchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, P. Spellman, Christopher Benz, Joshua M. Stuart, Christopher K. Wong, Christina S. F. Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, A I Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Birch Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Marco A. Marra, Marco A. Marra, Michael Mayo, Richard A. Moore, Karen L. 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 B. Gabriel, Gavin Ha, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Juliann Shih, Raju Kucherlapati, Raju Kucherlapati, Baylin SB, Leslie Cope, Ludmila Danilova, Moiz Bootwalla, Phillip H. Lai, Dennis T. Maglinte, Daniel J. Weisenberger, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, 孟绍武, Piotr A. Mieczkowski, Lisle E. Mose, Charles M. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Huihui Fan, Toshinori Hinoue, P O Laird, Hui Shen, Wanding Zhou, Michelle Bellair, Kyle R. Covington, Kyle Covington, Chad J. Creighton, Huyen Dinh, Harshavardhan Doddapaneni, LA Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Xiuping Liu, Xiuping Liu, Margaret Morgan, Donna Marie Muzny, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Min Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian M. Hess, Elizabeth L. Appelbaum, Matthew G. Cordes, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Robert S. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel F. Crain, Erin Curley, Johanna Gardner, Kevin W. Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Troy Shelton, Troy Shelton, Mark 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 Corcoran, Tony Costello, Christopher M. Hovens, Ana Carolina de Carvalho, A. C. de P. Carvalho, José H. Fregnani, Adhemar Longatto‐Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C. S. Silveira, Daniel Onofre Vidal, Andrew Burnette, J Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Andry Cd, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, G R Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Stuart Berkowitz, Daniel Cramer, Colleen Feltmate, Horowitz Nh, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz‐Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, J R Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson, R.J. Mural, Stella Somiari, Aleš Vícha, Tomáš Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, McGraw Mj, Susan M. Staugaitis, J. Chabot, Hanina Hibshoosh, Antonia Sepúlveda, Tao Su, T Wang, Olga L. Voronina, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman‐Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell D. Bigner, Eric Lipp, Jeffrey Marks, S. J. McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong Moon 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, Mattei Lf, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Robert Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, D. Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Bubley Gj, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Aymerich Ml, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bùi Đức Phú, Yufang Tang, Howard Colman, Kimberley Jane Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Alton Copland, Copland Jw, Michael Farnell, Thomas Flotte, Nasra H. Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla J. Kopp, Catherine Moser, MD David Nagorney, Daniel O'Brien, Brian Patrick O’Neill, TUSHAR PATEL, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert C. Smallridge, TC 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 Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Alexander J. Lazar, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, onathan Stretch, Maria Synott, John Thompson, James Wilmott, Hikmat Al-Ahmadie, Timothy A. Chan, R A Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas B. Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyễn Phi Hùng, ELECTRON KEBEBEW, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Worrell Rv, H. J. Yang, Marc D. Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey 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, Sébastien Gilbert, Jeremy R. Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bruno Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne‐Paule Gimenez‐Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kıvanç Birsoy, Gene Barnett, Cathy J. Brewer, C. E. Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy N. Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Junker Ks, Larsson Omberg, Mikhail Dinkin, G M Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Cottingham Sl, M V Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus‐Peter Janssen, Julia Slotta‐Huspenina, Mohamed H. Abdel‐Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Schoenfield Lj, Kelly Senecal, Paul Hansen, Paul Hansen, Lechan Rm, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin King Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas von Deimling, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Tina M. Knutson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Sally Nneoma Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne‐Marie Mes‐Masson, Fred Saad, Therese Bocklage, Lisa Landrum, R. S. Mannel, Kathleen Moore, Katherine Moxley, Postier Rg, Joan Walker, Rosemary Zuna, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlotti Cc, José Sebastião dos Santos, Rafael Kemp, Ajith Kumar Sankarankuty, Daniela Tirapelli, James Catto, Agnew Km, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, T. A. Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Korst Rj, Rathmell Wg, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John Dipersio, Bettina Drake, Ramaswamy Govindan, SHARON HEATH, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, Armaz Mariamidze, Ilya Shmulevich, Arvind Rao, Alexander J. Lazar, Ashish Sharma, Vésteinn Thórsson, Vésteinn Thórsson · 发表于：Cell Reports · 年份：2018 · DOI：10.1016/j.celrep.2018.03.086 · 被引用次数：1096 · 研究领域：Single-cell and spatial transcriptomics、Cell Image Analysis Techniques、Cancer Immunotherapy and Biomarkers

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.