Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade

Abstract

Blocking Programmed Death–1 (PD-1) can reinvigorate exhausted CD8 Tcells (TEX) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram TEX into durable memory Tcells (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 Tcells (TEFF) and TMEM cells that was minimally remodeled after PD-L1 blockade. This finding suggests that TEX are a distinct lineage of CD8 Tcells. 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.

Is autoimmunity the Achilles' heel of cancer immunotherapy?

“…For instance, CD8 + T cell exhaustion is frequently observed in chronic viral infections 58 . Moreover, PD-1 blockade seems to reactivate effector T cells through the targeting of certain transcriptional factors (i.e., nuclear factor kappa-light-chainenhancer of activated B cells, interferon regulatory factors 1 and 2, orphan nuclear receptor NR4A1, and B-lymphocyte-induced maturation protein 1) that cause a reengagement of the effector mechanisms in the epigenome of exhausted T cells 59 . CTLA-4 has also been found to have a clear role in multiple chronic infections, including HBV, HCV, and HIV, and its inhibition can increase the function of pathogen-specific T cells 60,61 .…”

Membranous and Cytoplasmic Expression of PD-L1 in Ovarian Cancer Cells

“…Blocking PD-1 can reinvigorate exhausted CD8 T cells and improve the control of cancer [35]. PD-1 pathway blockade also resulted in transcriptional rewiring and the reengagement of effector circuitry in the exhausted CD8 + T cells epigenetic landscape [36]. Here, tumour-bearing mice displayed an obvious increase of PD-1 + CD8 + T cell in tumour and spleen tissues.…”

β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity

“…Finally, we determined if p110δ and β-catenin inhibitors could be used to enrich and expand central memory cells from fully differentiated Th17 cultures. This question is important, as TILs from cancer patients are often fully differentiated or terminally exhausted, even after ACT or PD-1 blockade therapy (31)(32)(33). As numerous studies have shown that CD62L + cells exert long-lived immunity, it is essential to find ways to preserve them in cancer immunotherapy (34)(35)(36).…”