Souptik Barua1, Penny Fang2, Amrish Sharma3, Junya Fujimoto4, Ignacio Wistuba4, Arvind U K Rao5, Steven H Lin6. 1. Department of Electrical Engineering, Rice University, 6100 Main Street, Houston, TX, 77005, USA; Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA. 2. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA. 3. Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center,1515 Holcombe Boulevard, Houston, TX, 77030, USA. 4. Molecular Pathology, The University of Texas MD Anderson Cancer Center,1515 Holcombe Boulevard, Houston, TX, 77030, USA. 5. Department of Electrical Engineering, Rice University, 6100 Main Street, Houston, TX, 77005, USA; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA; Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA. Electronic address: aruppore@mdanderson.org. 6. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA; Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center,1515 Holcombe Boulevard, Houston, TX, 77030, USA. Electronic address: SHLin@mdanderson.org.
Abstract
OBJECTIVES: To determine the prognostic significance of spatial proximity of lung cancer cells and specific immune cells in the tumor microenvironment. MATERIALS AND METHODS: We probed formalin-fixed, paraffin-embedded (FFPE) tissue microarrays using a novel tyramide signal amplification multiplexing technique labelling CD8, CD4, Foxp3, and CD68+ cells. Each multiplex stained immunohistochemistry slide was digitally processed by Vectra INFORMS software, and an X- and Y-coordinate assigned to each labeled cell type. The abundance and spatial location of each cell type and their proximity to one another was analyzed using a novel application of the G-cross spatial distance distribution method which computes the probability of finding at least one immune cell of any given type within a rμm radius of a tumor cell. Cox proportional hazards multiple regression was used for multivariate analysis of the influence of proximity of lymphocyte types. RESULTS: Pathologic tumor specimens from 120 NSCLC patients with pathologic tumor stage I-III disease were analyzed. On univariate analysis, age (P = .0007) and number of positive nodes (P = .0014) were associated with overall survival. Greater area under the curve (AUC) of the G-cross function for tumor cell-Treg interactions was significantly associated with worse survival adjusting for age and number of positive nodes (HR 1.52 (1.11-2.07), P = .009). Greater G-cross AUC for T-reg-CD8 was significantly associated with better survival adjusting for age and number of positive lymph nodes (HR 0.96 (0.92-0.99), P = .042). CONCLUSION: Increased infiltration of regulatory T cells into core tumor regions is an independent predictor of worse overall survival in NSCLC. However, increased infiltration of CD8+ cytotoxic T cells among regulatory T cells seems to mitigate this effect and was significantly associated with better survival. Validation of the G-cross method of measuring spatial proximity between tumor and immune cell types and exploration of its use as a prognostic factor in lung cancer treatment is warranted.
OBJECTIVES: To determine the prognostic significance of spatial proximity of lung cancer cells and specific immune cells in the tumor microenvironment. MATERIALS AND METHODS: We probed formalin-fixed, paraffin-embedded (FFPE) tissue microarrays using a novel tyramide signal amplification multiplexing technique labelling CD8, CD4, Foxp3, and CD68+ cells. Each multiplex stained immunohistochemistry slide was digitally processed by Vectra INFORMS software, and an X- and Y-coordinate assigned to each labeled cell type. The abundance and spatial location of each cell type and their proximity to one another was analyzed using a novel application of the G-cross spatial distance distribution method which computes the probability of finding at least one immune cell of any given type within a rμm radius of a tumor cell. Cox proportional hazards multiple regression was used for multivariate analysis of the influence of proximity of lymphocyte types. RESULTS: Pathologic tumor specimens from 120 NSCLC patients with pathologic tumor stage I-III disease were analyzed. On univariate analysis, age (P = .0007) and number of positive nodes (P = .0014) were associated with overall survival. Greater area under the curve (AUC) of the G-cross function for tumor cell-Treg interactions was significantly associated with worse survival adjusting for age and number of positive nodes (HR 1.52 (1.11-2.07), P = .009). Greater G-cross AUC for T-reg-CD8 was significantly associated with better survival adjusting for age and number of positive lymph nodes (HR 0.96 (0.92-0.99), P = .042). CONCLUSION: Increased infiltration of regulatory T cells into core tumor regions is an independent predictor of worse overall survival in NSCLC. However, increased infiltration of CD8+ cytotoxic T cells among regulatory T cells seems to mitigate this effect and was significantly associated with better survival. Validation of the G-cross method of measuring spatial proximity between tumor and immune cell types and exploration of its use as a prognostic factor in lung cancer treatment is warranted.
Authors: Cécile Badoual; Stéphane Hans; José Rodriguez; Severine Peyrard; Christophe Klein; Nour El Houda Agueznay; Véronique Mosseri; Ollivier Laccourreye; Patrick Bruneval; Wolf H Fridman; Daniel F Brasnu; Eric Tartour Journal: Clin Cancer Res Date: 2006-01-15 Impact factor: 12.531
Authors: Luc Bron; Camilla Jandus; Snezana Andrejevic-Blant; Daniel E Speiser; Philippe Monnier; Pedro Romero; Jean-Paul Rivals Journal: Int J Cancer Date: 2012-10-03 Impact factor: 7.396
Authors: William J Grossman; James W Verbsky; Benjamin L Tollefsen; Claudia Kemper; John P Atkinson; Timothy J Ley Journal: Blood Date: 2004-07-06 Impact factor: 22.113
Authors: Jérôme Galon; Bernhard Mlecnik; Gabriela Bindea; Helen K Angell; Anne Berger; Christine Lagorce; Alessandro Lugli; Inti Zlobec; Arndt Hartmann; Carlo Bifulco; Iris D Nagtegaal; Richard Palmqvist; Giuseppe V Masucci; Gerardo Botti; Fabiana Tatangelo; Paolo Delrio; Michele Maio; Luigi Laghi; Fabio Grizzi; Martin Asslaber; Corrado D'Arrigo; Fernando Vidal-Vanaclocha; Eva Zavadova; Lotfi Chouchane; Pamela S Ohashi; Sara Hafezi-Bakhtiari; Bradly G Wouters; Michael Roehrl; Linh Nguyen; Yutaka Kawakami; Shoichi Hazama; Kiyotaka Okuno; Shuji Ogino; Peter Gibbs; Paul Waring; Noriyuki Sato; Toshihiko Torigoe; Kyogo Itoh; Prabhu S Patel; Shilin N Shukla; Yili Wang; Scott Kopetz; Frank A Sinicrope; Viorel Scripcariu; Paolo A Ascierto; Francesco M Marincola; Bernard A Fox; Franck Pagès Journal: J Pathol Date: 2014-01 Impact factor: 7.996
Authors: Kyle G Mitchell; Edwin R Parra; David B Nelson; Jiexin Zhang; Ignacio I Wistuba; Junya Fujimoto; Jack A Roth; Mara B Antonoff Journal: J Thorac Cardiovasc Surg Date: 2019-05-17 Impact factor: 5.209
Authors: Phyu P Aung; Edwin Roger Parra; Souptik Barua; Dawen Sui; Jing Ning; Barbara Mino; Debora Alejandra Ledesma; Jonathan L Curry; Priyadharsini Nagarajan; Carlos A Torres-Cabala; Eleni Efstathiou; Anh G Hoang; Michael K Wong; Jennifer A Wargo; Alexander J Lazar; Arvind Rao; Victor G Prieto; Ignacio Wistuba; Michael T Tetzlaff Journal: Clin Cancer Res Date: 2019-02-26 Impact factor: 12.531
Authors: Mohamed Amgad; Elisabeth Specht Stovgaard; Eva Balslev; Jeppe Thagaard; Weijie Chen; Sarah Dudgeon; Ashish Sharma; Jennifer K Kerner; Carsten Denkert; Yinyin Yuan; Khalid AbdulJabbar; Stephan Wienert; Peter Savas; Leonie Voorwerk; Andrew H Beck; Anant Madabhushi; Johan Hartman; Manu M Sebastian; Hugo M Horlings; Jan Hudeček; Francesco Ciompi; David A Moore; Rajendra Singh; Elvire Roblin; Marcelo Luiz Balancin; Marie-Christine Mathieu; Jochen K Lennerz; Pawan Kirtani; I-Chun Chen; Jeremy P Braybrooke; Giancarlo Pruneri; Sandra Demaria; Sylvia Adams; Stuart J Schnitt; Sunil R Lakhani; Federico Rojo; Laura Comerma; Sunil S Badve; Mehrnoush Khojasteh; W Fraser Symmans; Christos Sotiriou; Paula Gonzalez-Ericsson; Katherine L Pogue-Geile; Rim S Kim; David L Rimm; Giuseppe Viale; Stephen M Hewitt; John M S Bartlett; Frédérique Penault-Llorca; Shom Goel; Huang-Chun Lien; Sibylle Loibl; Zuzana Kos; Sherene Loi; Matthew G Hanna; Stefan Michiels; Marleen Kok; Torsten O Nielsen; Alexander J Lazar; Zsuzsanna Bago-Horvath; Loes F S Kooreman; Jeroen A W M van der Laak; Joel Saltz; Brandon D Gallas; Uday Kurkure; Michael Barnes; Roberto Salgado; Lee A D Cooper Journal: NPJ Breast Cancer Date: 2020-05-12
Authors: Naoto T Ueno; Savitri Krishnamurthy; Jennifer A Wargo; Elizabeth A Mittendorf; Sangeetha M Reddy; Alexandre Reuben; Souptik Barua; Hong Jiang; Shaojun Zhang; Linghua Wang; Vancheswaran Gopalakrishnan; Courtney W Hudgens; Michael T Tetzlaff; James M Reuben; Takahiro Tsujikawa; Lisa M Coussens; Khalida Wani; Yan He; Lily Villareal; Anita Wood; Arvind Rao; Wendy A Woodward Journal: Cancer Immunol Res Date: 2019-05-01 Impact factor: 11.151
Authors: Juha P Väyrynen; Mai Chan Lau; Koichiro Haruki; Sara A Väyrynen; Jeffrey A Meyerhardt; Marios Giannakis; Shuji Ogino; Jonathan A Nowak; Andressa Dias Costa; Jennifer Borowsky; Melissa Zhao; Kenji Fujiyoshi; Kota Arima; Tyler S Twombly; Junko Kishikawa; Simeng Gu; Saina Aminmozaffari; Shanshan Shi; Yoshifumi Baba; Naohiko Akimoto; Tomotaka Ugai; Annacarolina Da Silva; Mingyang Song; Kana Wu; Andrew T Chan; Reiko Nishihara; Charles S Fuchs Journal: Clin Cancer Res Date: 2020-05-21 Impact factor: 12.531
Authors: Ileana S Mauldin; Natasha D Sheybani; Samuel J Young; Richard J Price; Craig L Slingluff Journal: Methods Enzymol Date: 2019-06-29 Impact factor: 1.600
Authors: Giovanni Bocchialini; Ana-Iris Schiefer; Leonhard Müllauer; Jürgen Thanner; Jonas Bauer; Felizia Thaler; Maria Laggner; Cecilia Veraar; Walter Klepetko; Konrad Hötzenecker; José Ramon Matilla; Hendrik Jan Ankersmit; Bernhard Moser Journal: Br J Cancer Date: 2022-06-24 Impact factor: 9.075
Authors: Christopher M Wilson; Oscar E Ospina; Mary K Townsend; Jonathan Nguyen; Carlos Moran Segura; Joellen M Schildkraut; Shelley S Tworoger; Lauren C Peres; Brooke L Fridley Journal: Cancers (Basel) Date: 2021-06-17 Impact factor: 6.575