RESUMO
Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance1,2. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity3-6. However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8+ T cell function by enhancing JAK-STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994 ). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes.
Assuntos
Imunoterapia , Neoplasias , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteína Tirosina Fosfatase não Receptora Tipo 2 , Animais , Humanos , Camundongos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Inibidores de Checkpoint Imunológico , Imunoterapia/métodos , Interferons/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 2/antagonistas & inibidores , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
Epigenetic dysregulation is a defining feature of tumorigenesis that is implicated in immune escape1,2. Here, to identify factors that modulate the immune sensitivity of cancer cells, we performed in vivo CRISPR-Cas9 screens targeting 936 chromatin regulators in mouse tumour models treated with immune checkpoint blockade. We identified the H3K9 methyltransferase SETDB1 and other members of the HUSH and KAP1 complexes as mediators of immune escape3-5. We also found that amplification of SETDB1 (1q21.3) in human tumours is associated with immune exclusion and resistance to immune checkpoint blockade. SETDB1 represses broad domains, primarily within the open genome compartment. These domains are enriched for transposable elements (TEs) and immune clusters associated with segmental duplication events, a central mechanism of genome evolution6. SETDB1 loss derepresses latent TE-derived regulatory elements, immunostimulatory genes, and TE-encoded retroviral antigens in these regions, and triggers TE-specific cytotoxic T cell responses in vivo. Our study establishes SETDB1 as an epigenetic checkpoint that suppresses tumour-intrinsic immunogenicity, and thus represents a candidate target for immunotherapy.
Assuntos
Inativação Gênica , Histona-Lisina N-Metiltransferase/metabolismo , Neoplasias/genética , Neoplasias/imunologia , Animais , Antígenos Virais/imunologia , Sistemas CRISPR-Cas/genética , Cromatina/genética , Cromatina/metabolismo , Elementos de DNA Transponíveis/genética , Modelos Animais de Doenças , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologiaRESUMO
Glioblastoma (GBM) is the most common primary brain cancer, comprising half of all malignant brain tumors. Patients with GBM have a poor prognosis, with a median survival of 14-15 months. Current therapies for GBM, including chemotherapy, radiotherapy, and surgical resection, remain inadequate. Novel therapies are required to extend patient survival. Although immunotherapy has shown promise in other cancers, including melanoma and non-small lung cancer, its efficacy in GBM has been limited to subsets of patients. Identifying biomarkers of immunotherapy response in GBM could help stratify patients, identify new therapeutic targets, and develop more effective treatments. This article reviews existing and emerging biomarkers of clinical response to immunotherapy in GBM. The scope of this review includes immune checkpoint inhibitor and antitumoral vaccination approaches, summarizing the variety of molecular, cellular, and computational methodologies that have been explored in the setting of anti-GBM immunotherapies.
RESUMO
PURPOSE: To determine if an improvement in cord-level intraoperative neuromonitoring (IONM) data following data loss results in a reduced risk for new postoperative motor deficit in pediatric and adult spinal deformity surgery. METHODS: A consecutive series of 1106 patients underwent spine surgery from 2015 to 2023 by a single surgeon. Cord alerts were defined by Somatosensory-Evoked Potentials (SSEP; warning criteria: 10% increase in latency or > 50% loss in amplitude) and Motor-Evoked Potentials (MEP; warning criteria: 75% loss in amplitude without return to acceptable limits after stimulation up 100 V above baseline level). Timing of IONM loss and recovery, interventions, and baseline/postoperative day 1 (POD1) lower extremity motor scores were analyzed. RESULTS: IONM Cord loss was noted in 4.8% (53/11,06) of patients and 34% (18/53) with cord alerts had a POD1 deficit compared to preoperative motor exam. MEP and SSEP loss attributed to 98.1% (52/53) and 39.6% (21/53) of cord alerts, respectively. Abnormal descending neurogenic-evoked potential (DNEP) was seen in 85.7% (12/14) and detected 91.7% (11/12) with POD1 deficit. Abnormal wake-up test (WUT) was seen in 38.5% (5/13) and detected 100% (5/5) with POD1 deficit. Most cord alerts occurred during a three-column osteotomy (N = 23/53, 43%); decompression (N = 12), compression (N = 7), exposure (N = 4), and rod placement (N = 14). Interventions were performed in all 53 patients with cord loss and included removing rods/less correction (N = 11), increasing mean arterial pressure alone (N = 10), and further decompression with three-column osteotomy (N = 9). After intervention, IONM data improved in 45(84.9%) patients (Full improvement: N = 28; Partial improvement: 17). For those with full and partial IONM improvement, the POD1 deficit was 10.7% (3/28) and 41.2% (7/17), respectively. For those without any IONM improvement (15.1%, 8/53), 100% (8/8) had a POD1 deficit, P < 0.001. CONCLUSION: A full or partial improvement in IONM data loss after intraoperative intervention was significantly associated with a lower risk for POD1 deficit with an absolute risk reduction of 89.3% and 58.8%, respectively. All patients without IONM improvement had a POD1 neurologic deficit.
RESUMO
Neural stem cells (NSCs) in the adult and aged brain are largely quiescent, and require transcriptional reprogramming to re-enter the cell cycle. However, the mechanisms underlying these changes and how they are altered with age remain undefined. Here, we identify the chromatin accessibility differences between primary neural stem/progenitor cells in quiescent and activated states. These distinct cellular states exhibit shared and unique chromatin profiles, both associated with gene regulation. Accessible chromatin states specific to activation or quiescence are active enhancers bound by key pro-neurogenic and quiescence factors. In contrast, shared sites are enriched for core promoter elements associated with translation and metabolism. Unexpectedly, through integrated analysis, we find that many sites that become accessible during NSC activation are linked to gene repression and associated with pro-quiescence factors, revealing a novel mechanism that may preserve quiescence re-entry. Furthermore, we report that in aged NSCs, chromatin regions associated with metabolic and transcriptional functions bound by key pro-quiescence transcription factors lose accessibility, suggesting a novel mechanism of age-associated NSC dysfunction. Together, our findings reveal how accessible chromatin states regulate the transcriptional switch between NSC quiescence and activation, and how this switch is affected with age.