Pan-cancer immune and stromal deconvolution predicts clinical outcomes and mutation profiles

Bhavneet Bhinder; Verena Friedl; Sunantha Sethuraman; Davide Risso; Kami E Chiotti; R Jay Mashl; Kyle P Ellrott; Jordan A Lee; Christopher K Wong; Kofi Gyan; Aditya Deshpande; Marcin Imielinski; Rohan Bareja; Josh Stuart; Myron Peto; Katherine A Hoadley; Alexander J Lazar; Andrew D Cherniack; Jingchun Zhu; Shaolong Cao; Mark Rubin; Wenyi Wang; Oliver F Bathe; Nicolas Robine; Li Ding; Peter W Laird; Wanding Zhou; Hui Shen; Vésteinn Thorsson; Jen Jen Yeh; Matthew H Bailey; Daniel Cui Zhou; Xianlu L Peng; Mary Goldman; Yongsheng Li; Anil Korkut; Nidhi Sahni; D Neil Hayes; Michael K A Mensah; Ina Felau; Anab Kemal; Samantha Caesar-Johnson; John A Demchok; Liming Yang; Martin L Ferguson; Roy Tarnuzzer; Zhining Wang; Jean C Zenklusen; Cancer Genome Atlas Analysis Network; Paul Spellman; Olivier Elemento

doi:10.1038/s41598-025-09075-y

Pan-cancer immune and stromal deconvolution predicts clinical outcomes and mutation profiles

Sci Rep. 2025 Jul 4;15(1):23921. doi: 10.1038/s41598-025-09075-y.

Authors

Bhavneet Bhinder^{1

2}, Verena Friedl^{3

4}, Sunantha Sethuraman⁵, Davide Risso⁶, Kami E Chiotti⁷, R Jay Mashl^{5

8}, Kyle P Ellrott⁹, Jordan A Lee⁹, Christopher K Wong^{3

4}, Kofi Gyan^{1

2}, Aditya Deshpande^{1

2}, Marcin Imielinski^{1

2}, Rohan Bareja^{1

2}, Josh Stuart⁴, Myron Peto⁷, Katherine A Hoadley¹⁰, Alexander J Lazar¹¹, Andrew D Cherniack^{12

13}, Jingchun Zhu⁴, Shaolong Cao¹⁴, Mark Rubin¹⁵, Wenyi Wang¹⁴, Oliver F Bathe^{16

17}, Nicolas Robine¹⁸, Li Ding^{5

8}, Peter W Laird¹⁹, Wanding Zhou¹⁹, Hui Shen¹⁹, Vésteinn Thorsson²⁰, Jen Jen Yeh²¹, Matthew H Bailey^{5

8}, Daniel Cui Zhou^{5

8}, Xianlu L Peng²¹, Mary Goldman⁴, Yongsheng Li²², Anil Korkut¹⁴, Nidhi Sahni²³, D Neil Hayes²⁴, Michael K A Mensah²⁵, Ina Felau²⁵, Anab Kemal²⁵, Samantha Caesar-Johnson²⁵, John A Demchok²⁵, Liming Yang²⁵, Martin L Ferguson²⁵, Roy Tarnuzzer²⁵, Zhining Wang²⁵, Jean C Zenklusen²⁵; Cancer Genome Atlas Analysis Network; Paul Spellman^#²⁶, Olivier Elemento^#^{27

28}

Collaborators

Cancer Genome Atlas Analysis Network:
Adam Margolin, Alana Weinstein, Andrea Sboner, Andrew Blair, Angela Brooks, Benjamin Berman, Benjamin Raphael, Brian Craft, Dante Bortone, David Heimain, David Gibbs, David Haan, Doron Betel, Duncan McColl, Emek Demir, Faeze Brahman, Farshad Farshidfar, Gaddy Getz, Galen Gao, Gordon Robertson, Huy Dinh, Hyo Young Choi, Ilya Shmulevich, Ioannis Anastopoulous, Jasmine Yang, Jeff Damrauer, Ken Chen, Lauren Sanders, Lee Cooper, Liang-Bo Wang, Matt Reyna, Mike Noble, Mohammed El-Kebir, Molly Zhang, Nicole Yeager, Paul Little, Richard Moffitt, Sam Meier, Teresa Swatloski, Theo Knijnenburg, Thomas Matthew, Vicky Chen, Vlado Uzunangelov, Xinghua Lu, Yige Wu, Yulia Newton, Zeya Wang

Affiliations

¹ Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA.
² Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, 10021, USA.
³ Biomolecular Engineering Department, School of Engineering, University of California, Santa Cruz, Santa Cruz, CA, 95064, USA.
⁴ UC Santa Cruz Genomics Institute, Santa Cruz, CA, 95064, USA.
⁵ Division of Oncology, Department of Medicine, Washington University in St. Louis, 4515 McKinley Dr, St. Louis, MO, 63110, USA.
⁶ Department of Statistical Sciences, University of Padova, Via C. Battisti 241, 35121, Padua, Italy.
⁷ Department of Molecular and Medical Genetics, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA.
⁸ McDonnell Genome Institute, 4444 Forest Park Ave Washington University, St. Louis, MO, 63108, USA.
⁹ Department of BioMedical Engineering, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA.
¹⁰ Lineberger Comprehensive Cancer Center, Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
¹¹ Departments of Pathology, Genomics Medicine, Dermatology, & Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd-Unit 85, Houston, TX, 77030, USA.
¹² Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
¹³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
¹⁴ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, TX, 77030, USA.
¹⁵ Department for BioMedical Research, University of Bern, Bern, 3012, Switzerland.
¹⁶ Division of Surgical Oncology, Tom Baker Cancer Centre, 1331 - 29Th St NW, Calgary, AB, T2N 4N2, Canada.
¹⁷ Departments of Surgery and Oncology, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4Z6, Canada.
¹⁸ New York Genome Center, Computational Biology, 101 Avenue of the Americas, New York, NY, 10013, USA.
¹⁹ Van Andel Institute, 333 Bostwick AVE NE, Grand Rapids, MI, 49503, USA.
²⁰ Institute for Systems Biology, 401 Terry Avenue N, Seattle, WA, 98109, USA.
²¹ Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA.
²² Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
²³ Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, 1808 Park Rd 1C, Smithville, TX, 78957, USA.
²⁴ University of Tennessee Health Sciences Center, Memphis, TN, 38103, USA.
²⁵ National Cancer Institute, 31 Center Dr, 3A20, Bethesda, MD, 20892, USA.
²⁶ Department of Molecular and Medical Genetics, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA. spellmap@ohsu.edu.
²⁷ Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA. ole2001@med.cornell.edu.
²⁸ Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, 10021, USA. ole2001@med.cornell.edu.

^# Contributed equally.

Abstract

Traditional gene expression deconvolution methods assess a limited number of cell types, therefore do not capture the full complexity of the tumor microenvironment (TME). Here, we integrate nine deconvolution tools to assess 79 TME cell types in 10,592 tumors across 33 different cancer types, creating the most comprehensive analysis of the TME. In total, we found 41 patterns of immune infiltration and stroma profiles, identifying heterogeneous yet unique TME portraits for each cancer and several new findings. Our findings indicate that leukocytes play a major role in distinguishing various tumor types, and that a shared immune-rich TME cluster predicts better survival in bladder cancer for luminal and basal squamous subtypes, as well as in melanoma for RAS-hotspot subtypes. Our detailed deconvolution and mutational correlation analyses uncover 35 therapeutic target and candidate response biomarkers hypotheses (including CASP8 and RAS pathway genes).

Keywords: Cell type estimation; Deconvolution; Immune cells; Integrated scores; Pan-cancer analysis; Somatic mutations; Stroma; Survival; Tumor microenvironment; Tumor progression; iScores.

MeSH terms

Biomarkers, Tumor / genetics
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Mutation*
Neoplasms* / genetics
Neoplasms* / immunology
Neoplasms* / pathology
Prognosis
Stromal Cells / immunology
Stromal Cells / metabolism
Stromal Cells / pathology
Tumor Microenvironment* / genetics
Tumor Microenvironment* / immunology

Substances

Biomarkers, Tumor

Abstract

MeSH terms

Substances

Grants and funding