title: Guidance Molecule SEMA3A Restricts Tumor Growth by Differentially Regulating the Proliferation of Tumor-Associated Macrophages.
abstract: Accumulation of tumor-associated macrophages (TAM) correlates with malignant progression, immune suppression, and poor prognosis. In this study, we defined a critical role for the cell-surface guidance molecule SEMA3A in differential proliferative control of TAMs. Tumor cell-derived SEMA3A restricted the proliferation of protumoral M2 macrophages but increased the proliferation of antitumoral M1, acting through the SEMA3A receptor neuropilin 1. Expansion of M1 macrophages in vivo enhanced the recruitment and activation of natural killer (NK) cells and cytotoxic CD8(+) T cells to tumors, inhibiting their growth. In human breast cancer specimens, we found that immunohistochemical levels of SEMA3A correlated with the expression of genes characteristic of M1 macrophages, CD8(+) T cells, and NK cells, while inversely correlating with established characters of malignancy. In summary, our results illuminate a mechanism whereby the TAM phenotype is controlled and identify the cell-surface molecule SEMA3A as a candidate for therapeutic targeting. Cancer Res; 76(11); 3166-78. ©2016 AACR.
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden.
authors.forename: Majken
authors.initials: M
authors.lastname: Wallerius
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Wallmann
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden.
authors.forename: Margarita
authors.initials: M
authors.lastname: Bartish
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Östling
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden.
authors.forename: Artur
authors.initials: A
authors.lastname: Mezheyeuski
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Tobin
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Nygren
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden.
authors.forename: Pradeepa
authors.initials: P
authors.lastname: Pangigadde
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden.
authors.forename: Paola
authors.initials: P
authors.lastname: Pellegrini
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Mario Leonardo
authors.initials: ML
authors.lastname: Squadrito
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pontén
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden. Department of Clinical Pathology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Hartman
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden. Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Bergh
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden.
authors.forename: Angelo
authors.initials: A
authors.lastname: De Milito
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Michele
authors.initials: M
authors.lastname: De Palma
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden.
authors.forename: Arne
authors.initials: A
authors.lastname: Östman
authors.affiliation: Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
authors.forename: John
authors.initials: J
authors.lastname: Andersson
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden. charlotte.rolny@ki.se.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Rolny
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007694:Killer Cells, Natural / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D060787:Neoplasm Grading; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D012333:RNA, Messenger; D040121:Semaphorin-3A; D039942:Neuropilin-1