Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells

Abstract

Although immune mechanisms can suppress tumour growth1,2, tumours establish potent, overlapping mechanisms that mediate immune evasion3,4,5,6. Emerging evidence suggests a link between angiogenesis and the tolerance of tumours to immune mechanisms7,8,9,10. Hypoxia, a condition that is known to drive angiogenesis in tumours, results in the release of damage-associated pattern molecules, which can trigger the rejection of tumours by the immune system11. Thus, the counter-activation of tolerance mechanisms at the site of tumour hypoxia would be a crucial condition for maintaining the immunological escape of tumours. However, a direct link between tumour hypoxia and tolerance through the recruitment of regulatory cells has not been established. We proposed that tumour hypoxia induces the expression of chemotactic factors that promote tolerance. Here we show that tumour hypoxia promotes the recruitment of regulatory T (Treg) cells through induction of expression of the chemokine CC-chemokine ligand 28 (CCL28), which, in turn, promotes tumour tolerance and angiogenesis. Thus, peripheral immune tolerance and angiogenesis programs are closely connected and cooperate to sustain tumour growth.

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Figure 1: CCL28 in tumours is upregulated by hypoxia.
Figure 2: Hypoxic tumour cells recruit CD4 + CD25 + FOXP3 + T reg cells through CCL28–CCR10.
Figure 3: CCL28 promotes tumour growth through attracting CCR10 + T reg cells.
Figure 4: T reg cells promote tumour angiogenesis.

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Acknowledgements

This work was supported by National Institutes of Health grant R01-CA116779; National Cancer Institute Ovarian SPORE grant P01-CA83638; and the Ovarian Cancer Research Fund. We thank M. Celeste Simon and S. Evans for generous help with the hypoxia studies; M. Feldman and the University of Pennsylvania Tumor Tissue & Biospecimen Bank for tumour processing; and G. Danet-Desnoyers and the University of Pennsylvania Xenograft Core Facility for NSG mice.

Author information

A.F. designed many of the experiments and conducted most of them, analysed the data and drafted the manuscript. X.P. assisted with the experiments. I.S.H. analysed and interpreted the tissue-based studies. A.B. conducted the initial hypoxia and qPCR array experiments. K.B. assisted with the experiments. L.-P.W. carried out the tissue stains. P.A.G. analysed the Affymetrix data. C.B.G. assisted with the tissue-based studies. P.L. prepared the tissue microarrays. L.Z. assisted with the study design and provided many cell lines. G.C. conceived and supervised the study, and wrote the manuscript.

Correspondence to George Coukos.

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The authors declare no competing financial interests.

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Facciabene, A., Peng, X., Hagemann, I. et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475, 226–230 (2011). https://doi.org/10.1038/nature10169

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