Guidance Molecule SEMA3A Restricts Tumor Growth by Differentially Regulating the Proliferation of Tumor-Associated Macrophages
2016 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 76, no 11, 3166-3178 p.Article in journal (Refereed) PublishedText
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.
Place, publisher, year, edition, pages
2016. Vol. 76, no 11, 3166-3178 p.
Cancer and Oncology
IdentifiersURN: urn:nbn:se:uu:diva-299729DOI: 10.1158/0008-5472.CAN-15-2596ISI: 000378060900009PubMedID: 27197153OAI: oai:DiVA.org:uu-299729DiVA: diva2:949996
FunderSwedish Cancer Society, 2013/852 2012/415 2013/771Swedish Research Council, 2013-5982Swedish Society for Medical Research (SSMF)The Karolinska Institutet's Research FoundationKnut and Alice Wallenberg Foundation