Understanding and targeting epigentic regulation of immune evasion in prostate cancer

PROJECT SUMMARY/ABSTRACT Immune checkpoint inhibitor (ICI)-based therapy revolutionized cancer treatment; however, prostate cancer (PCa) is known to be generally immune-cold and refractory to ICI in non-selective patients. A lack of cytotoxic T lymphocyte (CTL) infiltration and the enrichment of myeloid-derived suppressor cells (MDSCs) contribute to immune evasion in PCa. Exact mechanisms that shape PCa’s tumor immune microenvironment (TIME) remain poorly understood. Recent studies point to critical involvement of epigenetic regulators. ~8% of the human genome are endogenous retrotransposons (ERVs), which are normally silenced by epigenetic mechanisms, notably, histone H3 lysine 9 trimethylation (H3K9me3). We recently identify TNRC18, an under-studied epigenetic factor, to be a new H3K9me3 reader that mediates ERV silencing. TNRC18 directly binds H3K9me3 via a C-terminal BAH domain and uses its N-terminal segment for recruiting corepressor such as HDAC. In the TCGA PCa patient dataset, we observe a significant negative correlation between TNRC18 expression and anti-tumor immune response, which indicates TNRC18 epigenetically modulates immunity. Our preliminary results collected from both human and mouse PCa cell models now show that TNRC18 knockout (KO) or loss- of-function (LOF) mutation activates ERVs and immune activation-related genes (such as CXCL10), which induces viral mimicry and immune activation. Combined scRNA-seq and flow cytometry-based analyses of immune cells in a murine PCa model further show that TNRC18 loss causes dramatic changes of TIME, notably, decrease of MDSCs and increase of CTLs; and in the same mouse PCa model, TNRC18 inactivation significantly sensitizes PCa to anti-PD1 treatment. Our hypotheses are that (i) in PCa, TNRC18 epigenetically silences the immune activation-related transcripts and immunogenic ERVs to promote immune evasion and that, (ii) conversely, TNRC18 LOF induces an ‘inflamed’ TIME, enabling the ICI-based therapy. To test these innovative hypotheses, we propose to use representative preclinic models to elucidate TNRC18’s tumor- intrinsic functions in regulating transcriptome and immunogenicity of PCa (aim 1); here, we use genome-wide profiling to dissect involvement of TNRC18 and associated Sin3/HDAC complex for epigenomic modulation and for silencing of immune activation pathways. We will also assess the TNRC18 LOF-induced viral mimicry effects on inducing interferon response and suppressing PCa growth. On a separate line of research (aim 2), we will define tumor-extrinsic effects of TNRC18 LOF on inducing an immuno-‘hot’ TIME, re-sensitizing PCa to ICIs; here, we will also examine the chemokine signaling pathways that mediate recruitment/infiltration of CTLs and MDSCs to PCa. The completion of the proposed research will not only gain novel mechanistic insights into epigenetic regulation of PCa’s immuno-‘cold’ characteristics but importantly will provide new therapeutic strategies that may be translated to the clinic in the future. The potential impact of the project is high.