Hypoxic Conditions Lead to Recruitment of T_reg Cells

Recent evidence has highlighted the complex interactions between tumors and the immune system. Although antitumor immunity can suppress tumor growth under some circumstances, tumors often evade the immune system, and certain types of immune cells have been shown to promote progression and metastasis. Hypoxia triggers both angiogenesis and the release of damage-associated pattern molecules, which can trigger an antitumor immune response. Facciabene and colleagues show that tumors in hypoxic conditions maintain immune escape by recruiting regulatory T (T_reg) cells through induction of CCL28. The authors first examined a panel of ovarian cancer cell lines and found that CCL28 was highly upregulated under hypoxic conditions by HIF1α. CCL28 correlated with HIF1α expression in ovarian cancer samples and overexpression was associated with a poor outcome in patients. In vitro and mouse experiments showed that CCL28 recruited T_reg cells via the CCR10 receptor, and that recruitment of these cells caused a significant acceleration in tumor growth. Further, the T_reg cells appeared to suppress effector T-cell function in the tumors. Consistent with reports of inverse correlation between tumor infiltrating T cells and angiogenesis, increased levels of the pro-angiogenic factor VEGFA were contributed by CCR10⁺ hematopoietic cells recruited into the tumors, and the authors also found that the T_reg cells themselves secreted VEGFA. These data show that hypoxic conditions result in recruitment of T_reg cells that induce a pro-angiogenic program and contribute to immune tolerance, thereby promoting tumor growth and progression.

Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang LP, et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 2011;475:226–30.

Note: Research Watch is written by Cancer Discovery Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.