De Novo Methylation Halts PD-1 Blockade–Mediated T-cell Revitalization

T cells enter a dysfunctional state known as exhaustion due to prolonged stimulation arising from the presence of chronic infections or cancer; as T cells become exhausted, they exhibit a hierarchical loss of T-cell effector cytokines and a progressive increase in inhibitory receptor expression. Although immune checkpoint blockade therapy targeting inhibitory receptors such as programmed cell death 1 (PD-1) has been clinically efficacious, a majority of patients fail to respond to anti–PD-1 therapy, in part due to the presence of irreversibly exhausted T cells. Recently, it has been shown that exhausted T cells exhibit distinct transcriptional and chromatin profiles from functional T cells and that the chromatin changes in exhausted T cells are irreversible. To identify the heritable epigenetic mechanisms driving T-cell exhaustion, Ghoneim and colleagues evaluated CD8⁺ T cells from conditional Dnmt3a knockout mice during chronic viral infection. Dnmt3a knockout CD8⁺ T cells harboring the loss of de novo methylation exhibited increased levels of effector cytokine production, whereas wild-type CD8⁺ T cells exhibited decreased cytokine production. Further, chronic, but not acute, stimulation of wild-type CD8⁺ T cells resulted in a progressive increase in cell-intrinsic de novo methylation, specifically of genes associated with immune-related pathways, during the effector-to-exhaustion transition to drive stable epigenetic reprogramming, terminal differentiation, and decreased proliferation. Anti–PD-L1 monotherapy induced both the rejuvenation and the expansion of Dnmt3a knockout CD8⁺ T cells but induced only the rejuvenation of wild-type CD8⁺ T cells, and sequential treatment with a DNA demethylating agent prior to anti–PD-1 blockade enhanced exhausted CD8⁺ T-cell rejuvenation compared to concurrent treatment of chronically infected mice and a syngeneic mouse model of prostate cancer. Together, these results elucidate the role of epigenetic reprogramming in T-cell exhaustion and suggest that treatment with DNA demethylating agents may enhance PD-1 blockade–mediated T-cell rejuvenation.

Ghoneim HE, Fan Y, Moustaki A, Abdelsamed HA, Dash P, Dogra P, et al. De novo epigenetic programs inhibit PD-1 blockade–mediated T cell rejuvenation. Cell 2017;170:142–57.e19.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.