APOBEC3B interaction with PRC2 modulates microenvironment to promote HCC progression

Abstract

ObjectiveAPOBEC3B (A3B), a cytidine deaminase acting as a contributor to the APOBEC mutation pattern in many kinds of tumours, is upregulated in patients with hepatocellular carcinoma (HCC). However, APOBEC mutation patterns are absent in HCC. The mechanism of how A3B affects HCC progression remains elusive.DesignA3B ­promoter luciferase reporter and other techniques were applied to elucidate mechanisms of A3B upregulation in HCC. A3B overexpression and knockdown cell models, immunocompetent and immune-deficient mouse HCC model were conducted to investigate the influence of A3B on HCC progression. RNA­seq, flow cytometry and other techniques were conducted to analyse how A3B modulated the cytokine to enhance the recruitment of myeloid­-derived suppressor cells (MDSCs) and tumour­-associated macrophages (TAMs).ResultsA3B upregulation through non-classical nuclear factor-κB (NF-κB)signalling promotes HCC growth in immunocompetent mice, associated with an increase of MDSCs, TAMs and programmed cell death1 (PD1) exprssed CD8+ T cells. A CCR2 antagonist suppressed TAMs and MDSCs infiltration and delayed tumour growth in A3B and A3BE68Q/E255Q­ expressing mouse tumours. Mechanistically, A3B upregulation in HCC depresses global H3K27me3 abundance via interaction with polycomb repressor complex 2 (PRC2) and reduces an occupancy of H3K27me3 on promoters of the chemokine CCL2 to recruit massive TAMs and MDSCs.ConclusionOur observations uncover a deaminase-independent role of the A3B in modulating the HCC microenvironment and demonstrate a proof for the concept of targeting A3B in HCC immunotherapy.

Isoform-specific characterization implicates alternative splicing inAPOBEC3Bas a mechanism restricting APOBEC-mediated mutagenesis

“…Most cancer types with a low proportion of nonmutagenic isoforms, specifically of A3B3, also had a higher rate of APOBEC-mediated mutation 150 burden 7,8 , with exceptions for tumors of KICH and LICH, in which APOBEC-signature mutations were negligible ( Figure S4). In these cancers, A3B might play a mitogenic rather than a mutagenic role as has been shown for hepatocellular carcinoma 29 and suggested for breast cancer 30 .…”

Reinvigorating exhausted CD8+ cytotoxic T lymphocytes in the tumor microenvironment and current strategies in cancer immunotherapy

“…65 Recently, we reported that the epigenetic modifications in cancer cells may facilitate massive trafficking of MDSCs and TAMs to the TME by regulating the release of CCL-2, leading to high expression of PD-1 on tumor-infiltrating CD8 + T cells and tumor progression. 66 In addition, some other soluble mediators are involved in the immune cell trafficking. Our latest work has uncovered a new mechanism by which depression-induced neuropeptide Y (NPY) secretion activates the IL-6-STAT3 signaling pathway and TAM infiltration.…”

“…Recruitment of the aforementioned immunosuppressive MDSCs, TAMs, and T reg cells to the TME is largely driven by the secretion pattern of chemokines, including CCL2, CCL5, CCL7, CXCL1, and CXCL12, and their interaction with the corresponding receptors 65 . Recently, we reported that the epigenetic modifications in cancer cells may facilitate massive trafficking of MDSCs and TAMs to the TME by regulating the release of CCL‐2, leading to high expression of PD‐1 on tumor‐infiltrating CD8 + T cells and tumor progression 66 . In addition, some other soluble mediators are involved in the immune cell trafficking.…”

The role of APOBEC3B in the development of hepatocellular carcinoma should be investigated with the consideration of hepatitis B virus evolution

“…In a recent study, Wang et al [8] revealed another important role of APOBEC3B in the cancer evolutionary process of mutation-selection-adaptation. Their study suggests that APOBEC3B can also contribute to the "selection" and "adaption" of malignant cells via facilitating the immune escape in a deaminaseindependent way.…”