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Epigenetic silencing of Th1 chemokines shapes tumor immunity, immunotherapy and patient outcome

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE71871 | GEO | 2015/08/11

SECONDARY ACCESSION(S): PRJNA292380

REPOSITORIES: GEO

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Epigenetic silencing of Th1 chemokines shapes tumor immunity, immunotherapy and patient outcome

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Epigenetic silencing of Th1 chemokines shapes tumor immunity, immunotherapy and patient outcome [shEZH2]

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

Project description:Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism. However, its role in cancer immunopathology and immunotherapy is poorly understood. Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T-cell tumour infiltration, slows down tumour progression, and improves the therapeutic efficacy of programmed death-ligand 1 (PD-L1; also known as B7-H1) checkpoint blockade and adoptive T-cell transfusion in tumour-bearing mice. Moreover, tumour EZH2 and DNMT1 are negatively associated with tumour-infiltrating CD8(+) T cells and patient outcome. Thus, epigenetic silencing of TH1-type chemokines is a novel immune-evasion mechanism of tumours. Selective epigenetic reprogramming alters the T-cell landscape in cancer and may enhance the clinical efficacy of cancer therapy.

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Project description:The presence of tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) affects cancer progression and immunotherapy response. The RNA m6A methylation, an epigenetic modification, has recently been found to play a pivotal role in shaping the TME. However, the role and underlying mechanisms by which RNA m6A methylation regulates TAMs function and anti-tumor immunity remain elusive. Here we show that depletion of YTHDF2, a well-known m6A reader, in TAMs suppresses tumor growth and metastasis. Myeloid YTHDF2 deficiency reprograms TAMs to anti-tumorigenic type and increases their cross-presentation ability, thereby enhancing CD8+T cell-mediated anti-tumor immunity. Transcriptome-wide screening identifies YTHDF2 deficiency facilitates anti-tumorigenic TAMs reprogramming through targeting IFN-γSTAT1 signaling. Selectively targeting YTHDF2 in TAMs using toll-like receptor 9 agonist - conjugated small interfering RNA against YTHDF2 effectively promotes anti-tumor immunity, restrains tumor growth, and enhances the efficacy of anti-PD-L1 therapy. Together, our findings suggest that YTHDF2 in TAMs might be a promising therapeutic target for cancer immunotherapy.

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