Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic viruses

Activating neutrophils by co-administration of immunogenic recombinant modified vaccinia virus Ankara and granulocyte colony-stimulating factor for the treatment of malignant peripheral nerve sheath tumor

“…We focused on MQ833 for the MPNST model using a well-characterized murine MPNST tumor-derived cell line SKP605 ( Nf1 -/- Cdkn2a -/- Cdkn2b -/- ) from skin-derived precursors (SKPs) of the C57BL/6J mice 31,32 . Two isogenic cell lines, SKP605 sg Con (PRC2-wt) and SKP605 sg Eed (PRC2-loss) were generated by using CRISPR-Cas9 to knock out the PRC2 core component Eed 4 . As previously described 30 , MQ833 was generated by deleting of both E3L and WR199 genes from the MQ710 genome and inserting of murine IL-12 expression cassette in the WR199 locus (Fig.…”

“…PRC2-loss occurs in more than 80% of all high-grade MPNSTs, and results in global loss of H3K27me2/3 and aberrant transcriptional activation of developmentally silenced master regulators, leading to enhanced cellular plasticity 2 . PRC2-loss in MPNST also leads to aberrant activation of multiple signaling pathways (e.g., WNT signaling), an “immune desert” tumor microenvironment, and primary resistance to immune checkpoint blockade (ICB) 4 .…”

BAP1 in cancer: epigenetic stability and genome integrity

“…2 ). Indeed, Yan and colleagues have recently demonstrated that the unbalanced activity of chromatin modifying factors like that caused by PRC2 inactivation, can strongly contributes to epigenetic reprogramming and transcriptional downregulation of genes involved in the immune cell recruitment, driving immune-desert tumour microenvironment [ 28 ]. Thus, identification and targeting of tumour-specific epigenetic dysregulations represent a possible therapeutic approach via administration of epidrugs as EZH2 (inhibitors of histone methyltransferase, core component of PRC2 complex), DNMT (DNA Methyltransferase), HDAC (Histone deacetylase) and BAP1 inhibitors [ 18 , 29 – 31 ].…”

“…Indeed, loss of BAP1 catalytic function titrates away both c-PRC1 and PRC2 complexes from their genomic loci causing derepression of Polycomb genes, the spreading and accumulation of H2AK119ub and H3K27me3 sustained by PRC1.3/5 at intergenic sites across the genome [8]. This results in a global chromatin compaction, reshaping of epigenetic landscape and aberrant transcriptome that associates with loss of cellular identity, oncogenesis, immune evasion and poor tumour response to immunotherapy [26][27][28] (Fig. 2).…”

The cancer epigenome: Non‐cell autonomous player in tumor immunity

“…Furthermore, identifying and leveraging such intrinsic oncogenic epigenetic molecules or machineries may provide a rational combinatorial therapeutic approach that improves the potency of cancer immunotherapy 11,13,14 . Although histone modifiers, such as histone methyltransferases, are emerging and particular druggable targets among epigenetic modulators, 15 the epigenetic dependency and program are diverse across developmental lineages or subtypes of cancer and are therefore context‐dependent 16 . In consequence, tracing the spatiotemporal evolutionary trajectory of cancer and immune cells is required to figure out key epigenetic molecules during a course of immunotherapy.…”