Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade
By Kristen E. Pauken, Morgan A. Sammons, P. Odorizzi, Sasikanth Manne, Jernej Godec, O. Khan, Adam M. Drake, Zeyu Chen, Debattama R. Sen, M. Kurachi and 9 more. Science, 2016
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Epigenetic profiling suggests that exhausted T cells are a distinct cell linage. The epigenetics of exhaustion During cancer or chronic infection, T cells become dysfunctional, eventually acquiring an “exhausted” phenotype. Immunotherapies aim to reverse this state. Using a mouse model of chronic infection, two studies now show that the epigenetic profile of exhausted T cells differs substantially from those of effector and memory T cells, suggesting that exhausted T cells are a distinct lineage (see the Perspective by Turner and Russ). Sen et al. defined specific functional modules of enhancers that are also conserved in exhausted human T cells. Pauken et al. examined the epigenetic profile of exhausted T cells after immunotherapy. Although there was transcriptional rewiring, the cells never acquired a memory T cell phenotype. Thus, epigenetic regulation may limit the success of immunotherapies. Science, this issue p. 1104, p. 1165; see also p. 1160 Blocking Programmed Death–1 (PD-1) can reinvigorate exhausted CD8 T cells (TEX) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram TEX into durable memory T cells (TMEM) is unclear. We found that reinvigoration of TEX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated TEX became reexhausted if antigen concentration remained high and failed to become TMEM upon antigen clearance. TEX acquired an epigenetic profile distinct from that of effector T cells (TEFF) and TMEM cells that was minimally remodeled after PD-L1 blockade. This finding suggests that TEX are a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the TEX epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies.
Subfields: Immunology
View Paper: https://www.semanticscholar.org/paper/3daaddab374f38531aee97b939c0f24518bae42d
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In Immunology
Citations in the corpus
- Mechanisms of resistance to immune checkpoint inhibitors (2018, background): “Exhausted PD-1þ CD8þ T cells display a distinct chromatin landscape compared with effector T cells and TEM cells (Pauken et al, 2016; Sen et al, 2016), and these epigenetically distinct T-cell states influence whether or not exhausted PD-1þ T cells can be reprogrammed to avoid terminal exhaustion…”
- Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade (2016, positive): “In chronic viral infection models, PD1 blockade of PD1highEomes+ TEX fails to convert these cells into durable and self-renewing memory T cells (Pauken et al., 2016).”
- TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion (2019, background): “Tox, Tox2, and Nr4a2 mRNAs were up-regulated in exhausted compared with effector cells in the LCMVmodel (13), and Tox, Tox2, and all Nr4a mRNAs were up-regulated in exhausted compared with naïve CD8 T cells (12) (SI Appendix, Fig.”
- The Principles of Engineering Immune Cells to Treat Cancer (2017, background): “Exhausted human and mouse T cells have sustained expression of PD-1 that is regulated by an exhaustionspecific enhancer that contains motifs from RAR, T-bet, and Sox3 (Sen et al., 2016), and the stability of the epigenetic changes leads to resistance to PD-1 antagonists (Pauken et al., 2016).”