title: Osteopontin shapes immunosuppression in the metastatic niche.
abstract: The matricellular protein osteopontin (OPN, Spp-1) is widely associated with cancer aggressiveness when produced by tumor cells, but its impact is uncertain when produced by leukocytes in the context of the tumor stroma. In a broad study using Spp1(-/-) mice along with gene silencing in tumor cells, we obtained evidence of distinct and common activities of OPN when produced by tumor or host cells in a spontaneously metastatic model of breast cancer. Different cellular localization of OPN is associated with its distinct activities, being mainly secreted in tumor cells while intracellular in myeloid cells. OPN produced by tumor cells supported their survival in the blood stream, whereas both tumor- and host-derived OPN, particularly from myeloid cells, rendered the metastatic site more immunosuppressive. Myeloid-derived suppressor cells (MDSC) expanded with tumor progression at both primary and lung metastatic sites. Of the expanded monocytic and granulocytic cell populations of MDSCs, the monocytic subset was the predominant source of OPN. In Spp1(-/-) mice, the inhibition of lung metastases correlated with the expansion of granulocyte-oriented MDSCs. Notably, monocytic MDSCs in Spp1(-/-) mice were less suppressive than their wild-type counterparts due to lower expression of arginase-1, IL6, and phospho-Stat3. Moreover, fewer regulatory T cells accumulated at the metastatic site in Spp1(-/-) mice. Our data find correlation with lung metastases of human mammary carcinomas that are associated with myeloid cells expressing OPN. Overall, our results unveiled novel functions for OPN in shaping local immunosuppression in the lung metastatic niche.
authors.affiliation: Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Sabina
authors.initials: S
authors.lastname: Sangaletti
authors.affiliation: Tumor Immunology Unit, Human Pathology Section, Department of Health Sciences, University of Palermo, Palermo, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Tripodo
authors.affiliation: Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Sandri
authors.affiliation: Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Torselli
authors.affiliation: Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Vitali
authors.affiliation: Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Ratti
authors.affiliation: Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Botti
authors.affiliation: Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Burocchi
authors.affiliation: Tumor Immunology Unit, Human Pathology Section, Department of Health Sciences, University of Palermo, Palermo, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Porcasi
authors.affiliation: Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tomirotti
authors.affiliation: Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. mariopaolo.colombo@istitutotumori.mi.it claudia.chiodoni@istitutotumori.mi.it.
authors.forename: Mario P
authors.initials: MP
authors.lastname: Colombo
authors.affiliation: Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. mariopaolo.colombo@istitutotumori.mi.it claudia.chiodoni@istitutotumori.mi.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Chiodoni
mesh_terms: D000818:Animals; D001119:Arginase / Q000276:immunology / Q000378:metabolism; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007165:Immunosuppression Therapy / Q000379:methods; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009362:Neoplasm Metastasis / Q000276:immunology* / Q000473:pathology*; D053495:Osteopontin / Q000276:immunology* / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D053495:Osteopontin; C544448:Arg1 protein, mouse; D001119:Arginase