Editors' ChoiceCancer Immunology

Metastatic trio: Macrophages, neutrophils, and γδ T cells

Sci. Signal.  23 Jun 2015:
Vol. 8, Issue 382, pp. ec168
DOI: 10.1126/scisignal.aac8311

The immune system plays critical roles in preventing tumor growth and metastasis; however, metastatic tumors can change this normal tumor-eliminating role into one that promotes metastasis. In a mouse model of spontaneous breast cancer, Coffelt et al. found systemic expansion of morphologically immature neutrophils with increased expression of the gene encoding inducible nitric oxide synthase (iNOS). Surgical removal of the primary tumor reduced the number of neutrophils. Depleting neutrophils from the tumor-bearing mice once the tumors were palpable, but not after surgical removal of the tumors, reduced the metastasis of the tumors to lymph nodes and lungs. Neutrophil depletion also enhanced the effector phenotype of CD8+ T cells from the lungs of tumor-bearing mice, which is consistent with a model in which the NO produced by the neutrophils suppresses effector T cell activity. Cytokine profiling of the mammary tumors revealed the increased abundance of cytokines, including interleukin-1β (IL-1β), that stimulate the release of IL-17, and tumor-associated macrophages were the most abundant cells that produced IL-1β. Depletion of γδ T cells from the tumor-bearing mice decreased the amount of IL-17 in the circulation, reduced the number of neutrophils and reversed the phenotypic changes in the neutrophils that had been induced by the tumors, and decreased metastasis to the lungs and lymph nodes. Thus, tumor-associated macrophages produce cytokines that stimulate γδ T cells, which in turn release factors that promote the production of neutrophils that suppress tumor-reactive cytotoxic T cell responses, enabling metastasis.

S. B. Coffelt, K. Kersten, C. W. Doornebal, J. Weiden, K. Vrijland, C.-S. Hau, N. J. M. Verstegen, M. Ciampricotti, L. J. A. C. Hawinkels, J. J. K. E. de Visser, IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522, 345–348 (2015). [PubMed]