Guidance Molecule SEMA3A Restricts Tumor Growth by Differentially Regulating the Proliferation of Tumor-Associated Macrophages

• Published in: Cancer research (Chicago, Ill.) Vol. 76; no. 11; pp. 3166 - 3178
• Main Authors: Wallerius, Majken, Wallmann, Tatjana, Bartish, Margarita, Östling, Jeanette, Mezheyeuski, Artur, Tobin, Nicholas P, Nygren, Emma, Pangigadde, Pradeepa, Pellegrini, Paola, Squadrito, Mario Leonardo, Pontén, Fredrik, Hartman, Johan, Bergh, Jonas, De Milito, Angelo, De Palma, Michele, Östman, Arne, Andersson, John, Rolny, Charlotte
• Format: Journal Article
• Language: English
• Published: United States 01.06.2016
• Subjects: Animals; Apoptosis; Blotting, Western; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; Cell Proliferation; Disease Progression; Female; Humans; Immunoenzyme Techniques; Killer Cells, Natural - metabolism; Killer Cells, Natural - pathology; Macrophages - metabolism; Macrophages - pathology; Medicin och hälsovetenskap; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Nude; Neoplasm Grading; Neuropilin-1 - genetics; Neuropilin-1 - metabolism; Prognosis; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Semaphorin-3A - genetics; Semaphorin-3A - metabolism; Survival Rate; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.can-15-2596

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.