Foxp3+ Tregs go against tumor in the "dark"

This week PNAS published follow-up study from Harvey Cantor's lab examining role of Helios (the Sun in Greek mythology) in Foxp3+ T_REG stability. In this new study they showed that antibody [anti-GITR]-mediated down-regulation of Helios in Foxp3+ T_REG causes them to acquire effector function and participate in anti-tumor response.

I will highlight relevant findings. The first finding was that mice with Helios-deficient Foxp3+ T_REG showed additional resistance to tumor (however, please note that tumor growth pattern and mice survival do not correlate in Helios^fl/fl.FoxP3-Cre mice).

Similar tumor growth retardation was observed in adoptive co-transfer experiment with WT T cells and Helios-KO Foxp3+ T_REG.

Mechanistically, Helios^fl/fl.FoxP3-cre T_REG up-regulated effector cytokines specifically at tumor site.

Finally, treatment of mice with antibody, DTA-1, directed to GITR (glucocorticoid induced TNF receptor), caused Helios down-regulation in FoxP3+ T_REG and improved tumor protection.

In summary, the authors proposed that therapeutic targeting of Helios expression in tumor-associated FoxP3+ T_REG could convert them from tolerogenic cells into anti-cancer fighting cells (however, please note the authors did not formally test whether anti-cancer effect of anti-GITR antibody was indeed mediated via its effect on Helios in FoxP3+ T_REG).

David Usharauli

Treg cells need a little Helios to function

Regulatory T cells (T_REG cells) are required to maintain tolerance to self and maybe even to foreign antigens, such as commensal bacteria-derived antigens. But how exactly T_REG cells keep other immune cells in check is not clear. 

Simply speaking, paradox with T_REG cells is that if T_REG cells are too potent or constantly "active" then they should prevent any immune response to any antigens. If T_REG cells are not constantly "active", then what signal(s) activate them? and if active T_REG cells are "inhibited" by infection and they regain their inhibitory functions once infection is cleared, how is such system coordinated? Basically, none of the available models can satisfactorily explain full spectrum of T_REG cells biology. Hence the reason why translation of basic knowledge about T_REG cells for clinical application is so slow.

So, every time we see new paper about T_REG cells we hope that we can acquire "some" missing information. In this regards, lets examine new paper in Science from Harvey Cantor's lab. There, the authors found that presence of transcription factor Helios is necessary to stabilize T_REG cells phenotype.

This is a simple, observation-type paper. Initially, the authors showed that starting from 5 months of age, mice deficient for Helios develop auto-antibodies to self antigens.

Next, using adoptive transfer experiments in combination with bone marrow chimera, the authors showed that Helios-deficient T_REG cells lacked suppressive function.

Finally, the authors showed that Helios-deficient T_REG cells displayed unstable phenotype and could be induced to express effector cytokines.

In summary, this study showed that Helios played an important role in stability of T_REG cells phenotype, especially during the ageing process. Of note, other studies with Helios-deficient mice did not observe the same phenotype. The authors claim that it has to do with the age difference of the experimental mice used in those earlier experiments. But genetic difference between mice colony itself or their gut flora could not be dismissed without proper experimentation.

David Usharauli