title: The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis.
abstract: Although distant metastases account for most of the deaths in cancer patients, fundamental questions regarding mechanisms that promote or inhibit metastasis remain unanswered. We show the impact of mutations, genomic instability, lymphatic and blood vascularization, and the immune contexture of the tumor microenvironment on synchronous metastases in large cohorts of colorectal cancer patients. We observed large genetic heterogeneity among primary tumors, but no major differences in chromosomal instability or key cancer-associated mutations. Similar patterns of cancer-related gene expression levels were observed between patients. No cancer-associated genes or pathways were associated with M stage. Instead, mutations of FBXW7 were associated with the absence of metastasis and correlated with increased expression of T cell proliferation and antigen presentation functions. Analyzing the tumor microenvironment, we observed two hallmarks of the metastatic process: decreased presence of lymphatic vessels and reduced immune cytotoxicity. These events could be the initiating factors driving both synchronous and metachronous metastases. Our data demonstrate the protective impact of the Immunoscore, a cytotoxic immune signature, and increased marginal lymphatic vessels, against the generation of distant metastases, regardless of genomic instability.
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, F-75006 Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, F-75006 Paris, France.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Mlecnik
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, F-75006 Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, F-75006 Paris, France.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Bindea
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, F-75006 Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, F-75006 Paris, France.
authors.forename: Amos
authors.initials: A
authors.lastname: Kirilovsky
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, F-75006 Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, F-75006 Paris, France. AstraZeneca, Cambridge CB4 OWG, UK.
authors.forename: Helen K
authors.initials: HK
authors.lastname: Angell
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Obenauf
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, F-75006 Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, F-75006 Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Tosolini
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, F-75006 Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, F-75006 Paris, France.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Church
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, F-75006 Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, F-75006 Paris, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Maby
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, F-75006 Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, F-75006 Paris, France.
authors.forename: Angela
authors.initials: A
authors.lastname: Vasaturo
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, F-75006 Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, F-75006 Paris, France.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Angelova
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, F-75006 Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, F-75006 Paris, France.
authors.forename: Tessa
authors.initials: T
authors.lastname: Fredriksen
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, F-75006 Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, F-75006 Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Mauger
authors.affiliation: Department of Medicine, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Waldner
authors.affiliation: Assistance Publique-Hopitaux de Paris, Department of General and Digestive Surgery, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Berger
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Speicher
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, F-75006 Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, F-75006 Paris, France. Assistance Publique-Hopitaux de Paris, Department of Immunology, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Pagès
authors.affiliation: MedImmune Ltd., Cambridge CB21 GGH, UK.
authors.forename: Viia
authors.initials: V
authors.lastname: Valge-Archer
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, F-75006 Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, F-75006 Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Galon
mesh_terms: D001808:Blood Vessels / Q000473:pathology; D002452:Cell Count; D016923:Cell Death; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D008208:Lymphatic System / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009362:Neoplasm Metastasis; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology*