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: Majken Wallerius, Tatjana Wallmann, Margarita Bartish, Jeanette Östling, Artur Mezheyeuski, Nicholas P Tobin, Emma Nygren, Pradeepa Pangigadde, Paola Pellegrini, Mario Leonardo Squadrito, Fredrik Pontén, Johan Hartman, Jonas Bergh, Angelo De Milito, Michele De Palma, Arne Östman, John Andersson, Charlotte Rolny
• Journal: Cancer research (Cancer Res) Vol. 76 Issue 11 Pg. 3166-78 (06 01 2016) ISSN: 1538-7445 [Electronic] United States
• PMID: 27197153 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• RNA, Messenger
• Semaphorin-3A
• Neuropilin-1

Topics

• Animals
• Apoptosis
• Blotting, Western
• Breast Neoplasms (genetics, metabolism, pathology)
• CD8-Positive T-Lymphocytes (metabolism, pathology)
• Cell Proliferation
• Disease Progression
• Female
• Humans
• Immunoenzyme Techniques
• Killer Cells, Natural (metabolism, pathology)
• Macrophages (metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C3H
• Mice, Nude
• Neoplasm Grading
• Neuropilin-1 (genetics, metabolism)
• Prognosis
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Semaphorin-3A (genetics, metabolism)
• Survival Rate
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays