Editors' ChoiceImmunotherapy

Reprograming Tregs to become tumor killers

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Science Translational Medicine  16 Dec 2015:
Vol. 7, Issue 318, pp. 318ec213
DOI: 10.1126/scitranslmed.aad9004

Immunotherapy is in the spotlight for developing new treatment approaches for cancer. In the quest for improved immunotherapeutics, recent successes have been achieved on enhancing T cell activation. However, often studies are based on only one cell phenotype, in which the effects on other cells in the immune milieu are overlooked.

Recent work by Akhmetzyanova et al. undertook the challenge of delving into the mechanism of how a CD8+ T cell agonist therapy also affects CD4+ T cells. The work focuses on agonist therapy for CD137, which is a regulator of T cell activation, proliferation, and cytokine production. Studies for this therapy have been focused on CD8+ T cells because CD137 is expressed at much higher levels by these cells than CD4+ T cells. This study focused on CD4+ T cells by utilizing CD8+-depleted mice and the Friend leukemia virus–induced FBL-3 tumor model. Upon anti-CD137 treatment, the authors found tumor rejection through a CD4+ T cell cytotoxic mechanism. They further examined the regulatory T cell (Treg) response because CD137 signaling is known to induce activation of natural Tregs. The novel aspect of the study was the finding that anti-CD137 therapy induced a population of Tregs with helper and cytotoxic functions. This population began as FoxP3 positive cells and gained cytotoxic function after exposure to anti-CD137. These cells retained FoxP3 expression, suggesting the need to be cautious about this marker as a sole marker of inhibitory Tregs. There is substantial value to the field in the approach for this work because mechanism of action on cells of the tumor microenvironment beyond the main cell target is sometimes overlooked in immunotherapy studies. However, the question remains, would this type of therapy only work in tumors that are very immunogenic, such as virus-induced tumors?

I. Akhmetzyanova et al., CD137 agonist therapy can reprogram regulatory T cells into cytotoxic CD4+ T cells with antitumor activity. J. Immunol. 10.4049/jimmunol.1403039 (2015). [Abstract]

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