RESUMO
Immune checkpoint blockade (ICB) has demonstrated clinical success in "inflamed" tumors with substantial T cell infiltrates, but tumors with an immune-desert tumor microenvironment (TME) fail to benefit. The tumor cell-intrinsic molecular mechanisms of the immune-desert phenotype remain poorly understood. Here, we demonstrated that inactivation of the polycomb-repressive complex 2 (PRC2) core components embryonic ectoderm development (EED) or suppressor of zeste 12 homolog (SUZ12), a prevalent genetic event in malignant peripheral nerve sheath tumors (MPNSTs) and sporadically in other cancers, drove a context-dependent immune-desert TME. PRC2 inactivation reprogramed the chromatin landscape that led to a cell-autonomous shift from primed baseline signaling-dependent cellular responses (e.g., IFN-γ signaling) to PRC2-regulated developmental and cellular differentiation transcriptional programs. Further, PRC2 inactivation led to diminished tumor immune infiltrates through reduced chemokine production and impaired antigen presentation and T cell priming, resulting in primary resistance to ICB. Intratumoral delivery of inactivated modified vaccinia virus Ankara (MVA) enhanced tumor immune infiltrates and sensitized PRC2-loss tumors to ICB. Our results identify molecular mechanisms of PRC2 inactivation-mediated, context-dependent epigenetic reprogramming that underline the immune-desert phenotype in cancer. Our studies also point to intratumoral delivery of immunogenic viruses as an initial therapeutic strategy to modulate the immune-desert TME and capitalize on the clinical benefit of ICB.
Assuntos
Neoplasias , Vírus , Cromatina , Humanos , Complexo Repressor Polycomb 2/genética , Microambiente Tumoral , Vírus/genéticaRESUMO
Polycomb repressive complex 2 (PRC2) has oncogenic and tumor-suppressive roles in cancer. There is clinical success of targeting this complex in PRC2-dependent cancers, but an unmet therapeutic need exists in PRC2-loss cancer. PRC2-inactivating mutations are a hallmark feature of high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive sarcoma with poor prognosis and no effective targeted therapy. Through RNAi screening in MPNST, we found that PRC2 inactivation increases sensitivity to genetic or small-molecule inhibition of DNA methyltransferase 1 (DNMT1), which results in enhanced cytotoxicity and antitumor response. Mechanistically, PRC2 inactivation amplifies DNMT inhibitor-mediated expression of retrotransposons, subsequent viral mimicry response, and robust cell death in part through a protein kinase R (PKR)-dependent double-stranded RNA sensor. Collectively, our observations posit DNA methylation as a safeguard against antitumorigenic cell-fate decisions in PRC2-loss cancer to promote cancer pathogenesis, which can be therapeutically exploited by DNMT1-targeted therapy. SIGNIFICANCE: PRC2 inactivation drives oncogenesis in various cancers, but therapeutically targeting PRC2 loss has remained challenging. Here we show that PRC2-inactivating mutations set up a tumor context-specific liability for therapeutic intervention via DNMT1 inhibitors, which leads to innate immune signaling mediated by sensing of derepressed retrotransposons and accompanied by enhanced cytotoxicity. See related commentary by Guil and Esteller, p. 2020. This article is highlighted in the In This Issue feature, p. 2007.
Assuntos
Antineoplásicos , Neoplasias , Neurofibrossarcoma , Carcinogênese/genética , Humanos , Mutação , Neoplasias/genética , Neurofibrossarcoma/diagnóstico , Neurofibrossarcoma/genética , Neurofibrossarcoma/patologia , Complexo Repressor Polycomb 2/genética , RetroelementosRESUMO
Deregulation of the BCL-2 family interaction network ensures cancer resistance to apoptosis and is a major challenge to current treatments. Cancer cells commonly evade apoptosis through upregulation of the BCL-2 anti-apoptotic proteins; however, more resistant cancers also downregulate or inactivate pro-apoptotic proteins to suppress apoptosis. Here, we find that apoptosis resistance in a diverse panel of solid and hematological malignancies is mediated by both overexpression of BCL-XL and an unprimed apoptotic state, limiting direct and indirect activation mechanisms of pro-apoptotic BAX. Both survival mechanisms can be overcome by the combination of an orally bioavailable BAX activator, BTSA1.2 with Navitoclax. The combination demonstrates synergistic efficacy in apoptosis-resistant cancer cells, xenografts, and patient-derived tumors while sparing healthy tissues. Additionally, functional assays and genomic markers are identified to predict sensitive tumors to the combination treatment. These findings advance the understanding of apoptosis resistance mechanisms and demonstrate a novel therapeutic strategy for cancer treatment.
Assuntos
Neoplasias , Proteína X Associada a bcl-2 , Proteína bcl-X , Compostos de Anilina/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Sinergismo Farmacológico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Sulfonamidas/farmacologia , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismoRESUMO
Glioblastoma (GBM) is the most common and aggressive of all brain tumors, with a median survival of only 14 months after initial diagnosis. Novel therapeutic approaches are an unmet need for GBM treatment. MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression at the post-transcriptional level. Several dysregulated miRNAs have been identified in all cancer types including GBM. In this study, we aimed to uncover the role of miR-143 in GBM cell lines, patient samples, and mouse models. Quantitative real-time RT-PCR of RNA extracted from formalin-fixed paraffin-embedded (FFPE) samples showed that the relative expression of miR-143 was higher in GBM patients compared to control individuals. Transient transfection of GBM cells with a miR-143 oligonucleotide inhibitor (miR-143-inh) resulted in reduced cell proliferation, increased apoptosis, and cell cycle arrest. SLC30A8, a glucose metabolism-related protein, was identified as a direct target of miR-143 in GBM cells. Moreover, multiple injections of GBM tumor-bearing mice with a miR-143-inh-liposomal formulation significantly reduced tumor growth compared to control mice. The reduced in vitro cell growth and in vivo tumor growth following miRNA-143 inhibition suggests that miR-143 is a potential therapeutic target for GBM therapy.
RESUMO
MicroRNAs (miRNAs) are a class of small noncoding RNAs that bind to 3'-untranslated (UTR) regions of target messenger RNAs to regulate protein synthesis. Reports have suggested that a set of specific miRNAs may be used as diagnostic and/or prognostic markers for astrocytoma grading. However, there are few studies of the specific miRNAs differentially expressed in each astrocytoma grade. MiRNA-containing total RNA was isolated from archived formalin-fixed, paraffin-embedded (FFPE) samples from WHO grade II-IV astrocytoma patients. The RNA was labeled and hybridized to Affymetrix miRNA 2.0 arrays. Statistical analysis identified several miRNAs differentially expressed in each astrocytoma grade. In particular, miR-27a, miR-210, and miR-1225-5p expression levels were able to differentiate grade IV from grade II and III astrocytomas as confirmed by real-time PCR. Kaplan-Meier survival analysis showed that disease progression occurred faster for Glioblastoma Multiforme (GBM) patients with a lower miR-27a expression level. Transfection of CRL-1690 GBM human cancer cells with a miR-27a oligonucleotide inhibitor followed by Real-time PCR identified six potential miR-27a target genes. Furthermore, the miR-27a oligonucleotide inhibitor induced CRL-1690 cell apoptosis. Taken together, our results provide additional miRNA signatures for distinguishing GBM from lower astrocytoma grades and suggest miR-27a as a prognostic and therapeutic target for GBM.