IL17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis

By S. Coffelt, K. Kersten, C. Doornebal, Jorieke Weiden, K. Vrijland, Cheei-Sing Hau, N. J. Verstegen, M. Ciampricotti, L. Hawinkels, J. Jonkers and 1 more. Nature, 2015

1,327 citations recorded by the source corpus.

Metastatic disease remains the primary cause of death for patients with breast cancer. The different steps of the metastatic cascade rely on reciprocal interactions between cancer cells and their microenvironment. Within this local microenvironment and in distant organs, immune cells and their mediators are known to facilitate metastasis formation. However, the precise contribution of tumour-induced systemic inflammation to metastasis and the mechanisms regulating systemic inflammation are poorly understood. Here we show that tumours maximize their chance of metastasizing by evoking a systemic inflammatory cascade in mouse models of spontaneous breast cancer metastasis. We mechanistically demonstrate that interleukin (IL)-1β elicits IL-17 expression from gamma delta (γδ) T cells, resulting in systemic, granulocyte colony-stimulating factor (G-CSF)-dependent expansion and polarization of neutrophils in mice bearing mammary tumours. Tumour-induced neutrophils acquire the ability to suppress cytotoxic T lymphocytes carrying the CD8 antigen, which limit the establishment of metastases. Neutralization of IL-17 or G-CSF and absence of γδ T cells prevents neutrophil accumulation and downregulates the T-cell-suppressive phenotype of neutrophils. Moreover, the absence of γδ T cells or neutrophils profoundly reduces pulmonary and lymph node metastases without influencing primary tumour progression. Our data indicate that targeting this novel cancer-cell-initiated domino effect within the immune system—the γδ T cell/IL-17/neutrophil axis—represents a new strategy to inhibit metastatic disease.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/9dc1bcba2342c3465b038466ad6f433f606ce29e

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In Immunology

1. S. Grivennikov
2. F. Greten
3. Hugo Gonzalez
4. Zena Werb
5. C. Hagerling
6. M. Karin
7. Pengfei Lu

In Oncology

1. S. Grivennikov
2. F. Greten
3. Hugo Gonzalez
4. Zena Werb
5. C. Hagerling
6. M. Karin
7. Pengfei Lu
8. M. Egeblad

Citations in the corpus

• Inflammation and Cancer: Triggers, Mechanisms and Consequences (2019, background): “…activation of neutrophils drives breast cancer metastasis through cellular interactions in the circulation and possibly via establishment of pre-metastatic niche (Coffelt et al., 2015), while lipopolysaccharide increases lung colonization and promotes tumor cell survival (Luo et al., 2004).”
• Characteristics and Significance of the Pre-metastatic Niche. (2016, background): “Furthermore, interleukin-1b (IL-1b)-elicited IL-17 production by gd T cells drives systemic expansion and polarization of neutrophils to form pre-metastatic niche and promotes subsequent breast cancer metastasis (Coffelt et al., 2015).”
• The microenvironmental landscape of brain tumors (2017, neutral): “These observations are reminiscent of what has been shown in other metastatic organs that are not subject to immune privilege (Casbon et al., 2015; Coffelt et al., 2015; Liu et al., 2016; Wculek and Malanchi, 2015), supporting the concept that, in the context of a tumor, the brain may be aberrantly…”
• EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, neutral): “Often mobilized through systemic signaling by a primary tumor, neutrophils can inhibit both cytotoxic CD8+ T cell responses (Coffelt et al., 2015) and the intraluminal clearance of carcinoma cells by NK cells (Spiegel et al., 2016).”
• Roles of the immune system in cancer: from tumor initiation to metastatic progression (2018, background): “Moreover, in response to the secretion of IL-7 by γδ T cells, neutrophils are recruited to the lungs, where they support the survival and proliferation of disseminated cancer cells by suppressing effector CD8 + T cells (Coffelt et al. 2015).”