Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy

Abstract

SummaryEpigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism1 However, its role in cancer immunopathology and immunotherapy is poorly understood. Using ovarian cancers as our model, we found that enhancer of zeste homolog 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase (DNMT) 1-mediated DNA methylation repress the tumor production of Th1-type chemokines CXCL9 and CXCL10, and subsequently determine effector T cell trafficking to the tumor microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T cell tumor infiltration, slows down tumor progression, and improves therapeutic efficacy of PD-L1 (B7-H1) checkpoint blockade2–4 and adoptive T cell transfusion5 in tumor bearing mice. Moreover, tumor EZH2 and DNMT1 are negatively associated with tumor infiltrating CD8+ T cells and patient outcome. Thus, epigenetic silencing of Th1-type chemokine is a novel tumor immune evasion mechanism. Selective epigenetic reprogramming alters T cell landscape6 in cancer and may enhance clinical efficacy of cancer therapy.

Is autoimmunity the Achilles' heel of cancer immunotherapy?

“…Hyperactivation of or mutations in EZH2 are found in a variety of malignancies 52 . However, EZH2 activity in tumor cells can shape the immune microenvironment of tumors by controlling the expression of chemokines 53 . Thus, in cancer, small molecules targeting proteins that are mutated in tumor cells could have dual effects: they might directly suppress proliferation or survival of cancer cells, and at the same time, they might modulate the anti-tumor immune response at the level of T reg cells.…”

Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade

“…PD-1 blockade therapies (Peng et al, 2015;Spranger et al, 2015). Unfortunately, limited approaches are available to increase lymphocyte infiltration without severe side effects.…”

The tumor microenvironment disarms CD8+ T lymphocyte function via a miR-26a-EZH2 axis

“…[19][20] Ovarian cancer cells employ the EZH2 machinery to suppress expression of the chemokines CXCL9 and CXCL10, which thereby serves as a prominent mechanism to exclude T helper type 1 (Th1) cells from the tumor. 21 Unexpectedly however, in CTLs, EZH2 was identified as an essential gene activator for promoting effector function. This was first identified in allogeneic CTL responses mediating graft-versus-host disease.…”