The Immune Landscape of Cancer

The Cancer Genome Atlas Research Network

Research output: Contribution to journalArticlepeer-review

898 Scopus citations

Abstract

We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes—wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant—characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field. Thorsson et al. present immunogenomics analyses of more than 10,000 tumors, identifying six immune subtypes that encompass multiple cancer types and are hypothesized to define immune response patterns impacting prognosis. This work provides a resource for understanding tumor-immune interactions, with implications for identifying ways to advance research on immunotherapy.

Original languageEnglish (US)
Pages (from-to)812-830.e14
JournalImmunity
Volume48
Issue number4
DOIs
StatePublished - Apr 17 2018

Bibliographical note

Funding Information:
We are grateful to all the patients and families who contributed to this study. We also thank the Office of Cancer Genomics at the NCI for organizational and logistical support of this study. The high-throughput analyses in this study were performed on the Institute for Systems Biology-Cancer Genomics Cloud (ISB-CGC) under contract number HHSN261201400007C and on the Seven Bridges Cancer Genomics Cloud under contract HHSN261201400008C , with federal funds from the National Cancer Institute, NIH, Department of Health and Human Services . Funding from the Cancer Research Institute is gratefully acknowledged, as is support from NCI through U54 HG003273 , U54 HG003067 , U54 HG003079 , U24 CA143799 , U24 CA143835 , U24 CA143840 , U24 CA143843 , U24 CA143845 , U24 CA143848 , U24 CA143858 , U24 CA143866 , U24 CA143867 , U24 CA143882 , U24 CA143883 , U24 CA144025 , and P30 CA016672 . The study was supported by W81XWH-12-2-0050 , HU0001-16-2-0004 from the US Department of Defense through the Henry M. Jackson Foundation for the Advancement of Military Medicine . We thank Peter Hammerman and Yasin Şenbabaoğlu for contributions in early phases of this work.

Funding Information:
We are grateful to all the patients and families who contributed to this study. We also thank the Office of Cancer Genomics at the NCI for organizational and logistical support of this study. The high-throughput analyses in this study were performed on the Institute for Systems Biology-Cancer Genomics Cloud (ISB-CGC) under contract number HHSN261201400007C and on the Seven Bridges Cancer Genomics Cloud under contract HHSN261201400008C, with federal funds from the National Cancer Institute, NIH, Department of Health and Human Services. Funding from the Cancer Research Institute is gratefully acknowledged, as is support from NCI through U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025, and P30 CA016672. The study was supported by W81XWH-12-2-0050, HU0001-16-2-0004 from the US Department of Defense through the Henry M. Jackson Foundation for the Advancement of Military Medicine. We thank Peter Hammerman and Yasin ?enbabao?lu for contributions in early phases of this work.

Funding Information:
We are grateful to all the patients and families who contributed to this study. We also thank the Office of Cancer Genomics at the NCI for organizational and logistical support of this study. The high-throughput analyses in this study were performed on the Institute for Systems Biology-Cancer Genomics Cloud (ISB-CGC) under contract number HHSN261201400007C and on the Seven Bridges Cancer Genomics Cloud under contract HHSN261201400008C, with federal funds from the National Cancer Institute, NIH, Department of Health and Human Services. Funding from the Cancer Research Institute is gratefully acknowledged, as is support from NCI through U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025, and P30 CA016672. The study was supported by W81XWH-12-2-0050, HU0001-16-2-0004 from the US Department of Defense through the Henry M. Jackson Foundation for the Advancement of Military Medicine. We thank Peter Hammerman and Yasin Şenbabaoğlu for contributions in early phases of this work.

Funding Information:
Michael Seiler, Peter G. Smith, Ping Zhu, Silvia Buonamici, and Lihua Yu are employees of H3 Biomedicine, Inc. Parts of this work are the subject of a patent application: WO2017040526 titled “Splice variants associated with neomorphic sf3b1 mutants.” Shouyoung Peng, Anant A. Agrawal, James Palacino, and Teng Teng are employees of H3 Biomedicine, Inc. Andrew D. Cherniack, Ashton C. Berger, and Galen F. Gao receive research support from Bayer Pharmaceuticals. Gordon B. Mills serves on the External Scientific Review Board of Astrazeneca. Anil Sood is on the Scientific Advisory Board for Kiyatec and is a shareholder in BioPath. Jonathan S. Serody receives funding from Merck, Inc. Kyle R. Covington is an employee of Castle Biosciences, Inc. Preethi H. Gunaratne is founder, CSO, and shareholder of NextmiRNA Therapeutics. Christina Yau is a part-time employee/consultant at NantOmics. Franz X. Schaub is an employee and shareholder of SEngine Precision Medicine, Inc. Carla Grandori is an employee, founder, and shareholder of SEngine Precision Medicine, Inc. Robert N. Eisenman is a member of the Scientific Advisory Boards and shareholder of Shenogen Pharma and Kronos Bio. Daniel J. Weisenberger is a consultant for Zymo Research Corporation. Joshua M. Stuart is the founder of Five3 Genomics and shareholder of NantOmics. Marc T. Goodman receives research support from Merck, Inc. Andrew J. Gentles is a consultant for Cibermed. Charles M. Perou is an equity stock holder, consultant, and Board of Directors member of BioClassifier and GeneCentric Diagnostics and is also listed as an inventor on patent applications on the Breast PAM50 and Lung Cancer Subtyping assays. Matthew Meyerson receives research support from Bayer Pharmaceuticals; is an equity holder in, consultant for, and Scientific Advisory Board chair for OrigiMed; and is an inventor of a patent for EGFR mutation diagnosis in lung cancer, licensed to LabCorp. Eduard Porta-Pardo is an inventor of a patent for domainXplorer. Han Liang is a shareholder and scientific advisor of Precision Scientific and Eagle Nebula. Da Yang is an inventor on a pending patent application describing the use of antisense oligonucleotides against specific lncRNA sequence as diagnostic and therapeutic tools. Yonghong Xiao was an employee and shareholder of TESARO, Inc. Bin Feng is an employee and shareholder of TESARO, Inc. Carter Van Waes received research funding for the study of IAP inhibitor ASTX660 through a Cooperative Agreement between NIDCD, NIH, and Astex Pharmaceuticals. Raunaq Malhotra is an employee and shareholder of Seven Bridges, Inc. Peter W. Laird serves on the Scientific Advisory Board for AnchorDx. Joel Tepper is a consultant at EMD Serono. Kenneth Wang serves on the Advisory Board for Boston Scientific, Microtech, and Olympus. Andrea Califano is a founder, shareholder, and advisory board member of DarwinHealth, Inc. and a shareholder and advisory board member of Tempus, Inc. Toni K. Choueiri serves as needed on advisory boards for Bristol-Myers Squibb, Merck, and Roche. Lawrence Kwong receives research support from Array BioPharma. Sharon E. Plon is a member of the Scientific Advisory Board for Baylor Genetics Laboratory. Beth Y. Karlan serves on the Advisory Board of Invitae.

Publisher Copyright:
© 2018 The Authors

Keywords

  • cancer genomics
  • immune subtypes
  • immuno-oncology
  • immunomodulatory
  • immunotherapy
  • integrative network analysis
  • tumor immunology
  • tumor microenvironment

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