Journal Article
. 2020 Jun; 8(1):e000491.
doi: 10.1136/jitc-2019-000491.

Lung metastases share common immune features regardless of primary tumor origin

Sandra García-Mulero 1 M Henar Alonso 1 Julián Pardo 2 Cristina Santos 3 Xavier Sanjuan 4 Ramón Salazar 3 Victor Moreno 1 Josep María Piulats 5 Rebeca Sanz-Pamplona 6 
  • PMID: 32591432
  •     42 References
  •     3 citations


Background: Only certain disseminated cells are able to grow in secondary organs to create a metastatic tumor. Under the hypothesis that the immune microenvironment of the host tissue may play an important role in this process, we have categorized metastatic samples based on their immune features.

Methods: Gene expression data of metastatic samples (n=374) from four secondary sites (brain, bone, liver and lung) were used to characterize samples based on their immune and stromal infiltration using gene signatures and cell quantification tools. A clustering analysis was done that separated metastatic samples into three different immune categories: high, medium and low.

Results: Significant differences were found between the immune profiles of samples metastasizing in distinct organs. Metastases in lung showed a higher immunogenic score than metastases in brain, liver or bone, regardless of their primary site of origin. Also, they preferentially clustered in the high immune group. Samples in this cluster exhibited a clear inflammatory phenotype, higher levels of immune infiltrate, overexpression of programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) pathways and upregulation of genes predicting clinical response to programmed cell death protein 1 (PD-1) blockade (T-cell inflammatory signature). A decision tree algorithm was used to select CD74 as a biomarker that identify samples belonging to this high-immune subtype of metastases, having specificity of 0.96 and sensitivity of 1.

Conclusions: We have found a group of lung-enriched metastases showing an inflammatory phenotype susceptible to be treated with immunotherapy.

Keywords: gene expression profiling; immunity; tumor microenvironment.

Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma.
David Liu, Bastian Schilling, +33 authors, Dirk Schadendorf.
Nat Med, 2019 Dec 04; 25(12). PMID: 31792460    Free PMC article.
Highly Cited.
Peroxiredoxin 2 specifically regulates the oxidative and metabolic stress response of human metastatic breast cancer cells in lungs.
V Stresing, E Baltziskueta, +11 authors, A Sierra.
Oncogene, 2012 Mar 21; 32(6). PMID: 22430214
Tumor metastasis: molecular insights and evolving paradigms.
Scott Valastyan, Robert A Weinberg.
Cell, 2011 Oct 18; 147(2). PMID: 22000009    Free PMC article.
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The tumor inflammation signature (TIS) is associated with anti-PD-1 treatment benefit in the CERTIM pan-cancer cohort.
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Deconvoluting tumor-infiltrating immune cells from RNA-seq data using quanTIseq.
Christina Plattner, Francesca Finotello, Dietmar Rieder.
Methods Enzymol, 2020 Mar 18; 636. PMID: 32178821
The secret second life of an innocent chaperone: the story of CD74 and B cell/chronic lymphocytic leukemia cell survival.
Idit Shachar, Michal Haran.
Leuk Lymphoma, 2011 Mar 23; 52(8). PMID: 21417823
Inferring tumour purity and stromal and immune cell admixture from expression data.
Kosuke Yoshihara, Maria Shahmoradgoli, +12 authors, Roel G W Verhaak.
Nat Commun, 2013 Oct 12; 4. PMID: 24113773    Free PMC article.
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Dvir Aran.
Methods Mol Biol, 2020 Mar 04; 2120. PMID: 32124326
Myc Cooperates with Ras by Programming Inflammation and Immune Suppression.
Roderik M Kortlever, Nicole M Sodir, +5 authors, Gerard I Evan.
Cell, 2017 Dec 02; 171(6). PMID: 29195074    Free PMC article.
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Surviving at a Distance: Organ-Specific Metastasis.
Anna C Obenauf, Joan Massagué.
Trends Cancer, 2015 Sep 01; 1(1). PMID: 28741564    Free PMC article.
Highly Cited. Review.
IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade.
Mark Ayers, Jared Lunceford, +12 authors, Terrill K McClanahan.
J Clin Invest, 2017 Jun 27; 127(8). PMID: 28650338    Free PMC article.
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T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.
Patrick A Ott, Yung-Jue Bang, +17 authors, Jared K Lunceford.
J Clin Oncol, 2018 Dec 18; 37(4). PMID: 30557521
Highly Cited.
The landscape of metastatic progression patterns across major human cancers.
Jan Budczies, Moritz von Winterfeld, +10 authors, Albrecht Stenzinger.
Oncotarget, 2014 Nov 18; 6(1). PMID: 25402435    Free PMC article.
Emerging Biological Principles of Metastasis.
Arthur W Lambert, Diwakar R Pattabiraman, Robert A Weinberg.
Cell, 2017 Feb 12; 168(4). PMID: 28187288    Free PMC article.
Highly Cited. Review.
Hallmarks of cancer: the next generation.
Douglas Hanahan, Robert A Weinberg.
Cell, 2011 Mar 08; 144(5). PMID: 21376230
Highly Cited. Review.
Liver immunology and its role in inflammation and homeostasis.
Mark W Robinson, Cathal Harmon, Cliona O'Farrelly.
Cell Mol Immunol, 2016 Apr 12; 13(3). PMID: 27063467    Free PMC article.
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Inhaled corticosteroids in COPD and the risk of lung cancer.
Yu Min Lee, Soo Jung Kim, Jin Hwa Lee, Eunhee Ha.
Int J Cancer, 2018 Jun 27; 143(9). PMID: 29943812
Vessel co-option in cancer.
Elizabeth A Kuczynski, Peter B Vermeulen, +2 authors, Andrew R Reynolds.
Nat Rev Clin Oncol, 2019 Mar 01; 16(8). PMID: 30816337
Highly Cited. Review.
The inflammatory chemokine CCL5 and cancer progression.
Donatella Aldinucci, Alfonso Colombatti.
Mediators Inflamm, 2014 Feb 14; 2014. PMID: 24523569    Free PMC article.
Highly Cited. Review.
Metastatic colonization by circulating tumour cells.
Joan Massagué, Anna C Obenauf.
Nature, 2016 Jan 23; 529(7586). PMID: 26791720    Free PMC article.
Highly Cited. Review.
Characteristics and clinical impacts of the immune environments in colorectal and renal cell carcinoma lung metastases: influence of tumor origin.
Romain Remark, Marco Alifano, +17 authors, Diane Damotte.
Clin Cancer Res, 2013 Jun 21; 19(15). PMID: 23785047
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Llipsy Santiago, Cheikh Menaa, +15 authors, Christopher J Froelich.
Arthritis Rheumatol, 2016 Sep 07; 69(2). PMID: 27598995
PD-1 blockade induces responses by inhibiting adaptive immune resistance.
Paul C Tumeh, Christina L Harview, +23 authors, Antoni Ribas.
Nature, 2014 Nov 28; 515(7528). PMID: 25428505    Free PMC article.
Highly Cited.
The Microenvironmental Landscape of Brain Tumors.
Daniela F Quail, Johanna A Joyce.
Cancer Cell, 2017 Mar 16; 31(3). PMID: 28292436    Free PMC article.
Highly Cited. Review.
Characteristics and Significance of the Pre-metastatic Niche.
Yang Liu, Xuetao Cao.
Cancer Cell, 2016 Nov 16; 30(5). PMID: 27846389
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Tumour-associated macrophages and cancer.
Jenny Cook, Thorsten Hagemann.
Curr Opin Pharmacol, 2013 Jun 19; 13(4). PMID: 23773801
Pulmonary alveolar macrophages contribute to the premetastatic niche by suppressing antitumor T cell responses in the lungs.
Sharad K Sharma, Navin K Chintala, +3 authors, Maciej M Markiewski.
J Immunol, 2015 Apr 26; 194(11). PMID: 25911761
Exosome-Mediated Metastasis: From Epithelial-Mesenchymal Transition to Escape from Immunosurveillance.
Nicholas Syn, Lingzhi Wang, +2 authors, Boon-Cher Goh.
Trends Pharmacol Sci, 2016 May 10; 37(7). PMID: 27157716
Highly Cited. Review.
Global patterns and trends in colorectal cancer incidence and mortality.
Melina Arnold, Mónica S Sierra, +3 authors, Freddie Bray.
Gut, 2016 Jan 29; 66(4). PMID: 26818619
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Shunsuke Kitajima, Rohit Thummalapalli, David A Barbie.
Semin Cell Dev Biol, 2016 Jun 15; 58. PMID: 27297136    Free PMC article.
Immunotherapy in triple-negative breast cancer.
Heather Katz, Mohamed Alsharedi.
Med Oncol, 2017 Dec 20; 35(1). PMID: 29255938
Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression.
Etienne Becht, Nicolas A Giraldo, +8 authors, Aurélien de Reyniès.
Genome Biol, 2016 Oct 22; 17(1). PMID: 27765066    Free PMC article.
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Inhaled corticosteroid use and risks of lung cancer and laryngeal cancer.
Chang-Hoon Lee, Min Kyung Hyun, +3 authors, Jae-Joon Yim.
Respir Med, 2013 Jun 19; 107(8). PMID: 23768737
Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
Aravind Subramanian, Pablo Tamayo, +8 authors, Jill P Mesirov.
Proc Natl Acad Sci U S A, 2005 Oct 04; 102(43). PMID: 16199517    Free PMC article.
Highly Cited.
Circulating and disseminated tumour cells - mechanisms of immune surveillance and escape.
Malte Mohme, Sabine Riethdorf, Klaus Pantel.
Nat Rev Clin Oncol, 2016 Nov 03; 14(3). PMID: 27644321
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Shiping Jiao, Sumit K Subudhi, +4 authors, Padmanee Sharma.
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Cell Rep, 2017 Jan 05; 18(1). PMID: 28052254
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Myeloid regulatory cells in tumor spreading and metastasis.
Anton A Keskinov, Michael R Shurin.
Immunobiology, 2014 Sep 03; 220(2). PMID: 25178934
The Untold Story of Granzymes in Oncoimmunology: Novel Opportunities with Old Acquaintances.
Maykel Arias, Luis Martínez-Lostao, +3 authors, Julián Pardo.
Trends Cancer, 2017 Jul 19; 3(6). PMID: 28718416
A Pan-cancer Landscape of Interactions between Solid Tumors and Infiltrating Immune Cell Populations.
David Tamborero, Carlota Rubio-Perez, +6 authors, Abel Gonzalez-Perez.
Clin Cancer Res, 2018 Apr 19; 24(15). PMID: 29666300
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KRAS mutation in lung metastases from colorectal cancer: prognostic implications.
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Metastatic Colonization: Escaping Immune Surveillance.
Julien Schaller, Judith Agudo.
Cancers (Basel), 2020 Nov 20; 12(11). PMID: 33207601    Free PMC article.
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