miR-155 harnesses Phf19 to potentiate cancer immunotherapy through epigenetic reprogramming of CD8+ T cell fate

Abstract

T cell senescence and exhaustion are major barriers to successful cancer immunotherapy. Here we show that miR-155 increases CD8 + T cell antitumor function by restraining T cell senescence and functional exhaustion through epigenetic silencing of drivers of terminal differentiation. miR-155 enhances Polycomb repressor complex 2 (PRC2) activity indirectly by promoting the expression of the PRC2-associated factor Phf19 through downregulation of the Akt inhibitor, Ship1. Phf19 orchestrates a transcriptional program extensively shared with miR-155 to restrain T cell senescence and sustain CD8 + T cell antitumor responses. These effects rely on Phf19 histone-binding capacity, which is critical for the recruitment of PRC2 to the target chromatin. These findings establish the miR-155–Phf19–PRC2 as a pivotal axis regulating CD8 + T cell differentiation, thereby paving new ways for potentiating cancer immunotherapy through epigenetic reprogramming of CD8 + T cell fate.

Involvement of miR-142 and miR-155 in Non-Infectious Complications of CVID

“…Moreover, miR-155 in CD8 T cells decreases suppression of cytokine signaling 1 (SOCS1) activity, leading to an improved anticancer response, thus using both innate and adaptative immune cells [ 18 ]. Ji et al showed that miR-155 improves the antitumor response by epigenetically limiting CD8 + T cell differentiation and activity depletion [ 19 ].…”

The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+T cells

“…However, the exact mechanisms by which DOT1L affects EZH2/PRC2 activity are still unknown. Although PRC2 targets were derepressed, Ezh2 mRNA expression was only modestly reduced in Dot1L-KO peripheral T cells, suggesting that DOT1L not only affects expression of Ezh2 but might also be involved in other processes that regulate PRC2 activity, such as the stability, structure, recruitment, or localization of the PRC2 complex 59,62,91,92,93,94,95,96,97,98,99,100 . H3K79 methylation is not likely to promote H3K27 methylation directly at the level of nucleosomes because the modifications generally occur in different genic regions and mark different sets of genes (e.g.…”

“…5c), the Ezh2 gene was H3K79me2 methylated (Sup Fig. 5d), and Dot1L-KO mice share several T-cell phenotypes with Ezh2-KO mice 40,60 , although this is dependent on the mouse model used [61][62][63] . To further investigate the idea that misregulation of PRC2 targets could be one of the downstream consequences of loss of DOT1L in CD8 + T cells, we compared the gene expression changes in an Ezh2-KO model 61 with those seen in Dot1L-KO CD8 + T cells.…”

Immunobiology of chimeric antigen receptor T cells and novel designs

“…Beyond TET2, other regulators of T cell function and persistence have been targeted in models of adoptive immunotherapy. Enhanced in vivo function, proliferation and persistence of T cells has been achieved in a model of immunotherapy for melanoma by altering the polycomb repressor complex 2 axis through the expression of miR‐155 in T cells . Similarly, enhancements in T cell immunotherapy have been demonstrated by the disruption of negative regulators of T cell signaling, such as Cbl‐b and Cish .…”