Resistance of naturally occurring regulatory T cells toward oxidative stress: possible link with intracellular catecholamine content and implications for cancer therapy

To the editor:

We read with interest the paper by Mougiakakos and colleagues documenting the reduced sensitivity of naturally occurring regulatory T lymphocytes (Tregs) toward oxidative stress-induced cell death.¹  The authors show in in vitro experiments that Tregs, compared with CD4⁺ T cells, are significantly more resistant to cytotoxicity induced by H₂O₂ or by coculture with granulocytes, and maintain their suppressive activity even with H₂O₂ levels lethal for effector CD4⁺ T cells. While we agree with the authors' hypothesis that this feature could contribute to explain Treg enrichment in cancer tissues, where increased levels of oxidative stress occur, we also wish to briefly discuss their observations in the light of other potentially relevant findings.

We previously reported that human Tregs contain high levels of the catecholamines (CA) dopamine, norepinephrine, and epinephrine.²  CA autooxidation occurs spontaneously, leading to formation of oxidative moieties, a process extensively investigated in neurodegeneration.³  In human lymphocytes, CA are synthesized and stored into the cells upon activation with mitogenic stimuli, and pharmacologic inhibition of their production results in reduced activation-induced apoptosis,⁴  in line with their cytotoxic potential. It is therefore not surprising that Tregs, which contain high amounts of CA,²  are also endowed with high levels of thiols,¹  conferring increased resistance to oxidative stress.

CA, however, also provide lymphocytes with an array of transmitters which can act in autocrine/paracrine fashion on cells bearing dopaminergic and/or adrenergic receptors. Indeed, we showed that in human lymphocytes, and in particular in Tregs, CA may be released upon appropriate treatments, eg with the CA-releasing agent reserpine²  or with type I interferons (IFNs).⁵  In Tregs, released CA (and in particular dopamine) act upon dopaminergic D1-like (possibly D5) receptors and subserve a feed-back loop leading to functional suppression of these cells.²  CA may play opposite roles in tumor growth: dopamine exerts antitumor effects, possibly through dopaminergic D2-like receptor-dependent inhibition of angiogenesis,⁶  whereas norepinephrine and epinephrine, acting through β-adrenoceptors, promote tumor growth and angiogenesis.⁷ 

Tumor-infiltrating Tregs may thus at the same time represent a source of endogenous CA and a target for exogenous drugs acting on CA receptors. Treatment with dopaminergic agents could result in reduction of both tumor neovascularization and of Treg-dependent local suppression of the immune response. CA release from Tregs themselves, triggered by use of a a CA-releasing agent such as reserpine, type I IFNs, or possibly other drugs such as buproprione,⁸  could provide an additional local source of dopamine, while inclusion of appropriate β-adrenoceptor antagonists (β-blockers) could block the potentially detrimental effects of norepinephrine and epinephrine released from sympathoadrenergic nerve endings and adrenals, as well as from tumor-infiltrating Tregs.

In summary, increased resistance of Tregs against oxidative stress¹  is in line with the high content of CA which occurs in these cells.²  CA, together with their receptors, may indeed represent a convenient target for novel immunomodulating and anticancer therapies, also in view of the wide array of dopaminergic and adrenergic agents in clinical use for different indications (in, eg, neurology, neuropsychiatry, cardiology) and of their usually good tolerability profile.