RESUMEN
Despite substantial progress in lung cancer immunotherapy, the overall response rate in patients with KRAS-mutant lung adenocarcinoma (LUAD) remains low. Combining standard immunotherapy with adjuvant approaches that enhance adaptive immune responses-such as epigenetic modulation of antitumor immunity-is therefore an attractive strategy. To identify epigenetic regulators of tumor immunity, we constructed an epigenetic-focused single guide RNA library and performed an in vivo CRISPR screen in a Kras G12D/Trp53 -/- LUAD model. Our data showed that loss of the histone chaperone Asf1a in tumor cells sensitizes tumors to anti-PD-1 treatment. Mechanistic studies revealed that tumor cell-intrinsic Asf1a deficiency induced immunogenic macrophage differentiation in the tumor microenvironment by upregulating GM-CSF expression and potentiated T-cell activation in combination with anti-PD-1. Our results provide a rationale for a novel combination therapy consisting of ASF1A inhibition and anti-PD-1 immunotherapy. SIGNIFICANCE: Using an in vivo epigenetic CRISPR screen, we identified Asf1a as a critical regulator of LUAD sensitivity to anti-PD-1 therapy. Asf1a deficiency synergized with anti-PD-1 immunotherapy by promoting M1-like macrophage polarization and T-cell activation. Thus, we provide a new immunotherapeutic strategy for this subtype of patients with LUAD.See related commentary by Menzel and Black, p. 179.This article is highlighted in the In This Issue feature, p. 161.
Asunto(s)
Adenocarcinoma del Pulmón/tratamiento farmacológico , Proteínas de Ciclo Celular/metabolismo , Resistencia a Antineoplásicos/genética , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Chaperonas Moleculares/metabolismo , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/patología , Animales , Sistemas CRISPR-Cas/genética , Proteínas de Ciclo Celular/genética , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Línea Celular Tumoral , Modelos Animales de Enfermedad , Epigénesis Genética/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Técnicas de Inactivación de Genes , Células HEK293 , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Chaperonas Moleculares/genética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Proteínas Proto-Oncogénicas p21(ras)/genética , ARN Guía de Kinetoplastida/genética , ARN Interferente Pequeño/metabolismo , RNA-Seq , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Cyclin-dependent kinase 7 (CDK7) is a central regulator of the cell cycle and gene transcription. However, little is known about its impact on genomic instability and cancer immunity. Using a selective CDK7 inhibitor, YKL-5-124, we demonstrated that CDK7 inhibition predominately disrupts cell-cycle progression and induces DNA replication stress and genome instability in small cell lung cancer (SCLC) while simultaneously triggering immune-response signaling. These tumor-intrinsic events provoke a robust immune surveillance program elicited by T cells, which is further enhanced by the addition of immune-checkpoint blockade. Combining YKL-5-124 with anti-PD-1 offers significant survival benefit in multiple highly aggressive murine models of SCLC, providing a rationale for new combination regimens consisting of CDK7 inhibitors and immunotherapies.
Asunto(s)
Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/genética , Inestabilidad Genómica , Neoplasias Pulmonares/genética , Carcinoma Pulmonar de Células Pequeñas/genética , Animales , Antineoplásicos/farmacología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD8-positivos/citología , Quimiocina CXCL9/metabolismo , Daño del ADN , Femenino , Humanos , Sistema Inmunológico , Inflamación , Interferón gamma/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Masculino , Ratones , Pruebas de Micronúcleos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Pirazoles/farmacología , Pirroles/farmacología , Transducción de Señal , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Quinasa Activadora de Quinasas Ciclina-DependientesRESUMEN
PD-1 immune checkpoint blockade occasionally results in durable clinical responses in advanced metastatic cancers. However, mechanism-based predictors of response to this immunotherapy remain incompletely characterized. We performed comprehensive genomic profiling on a tumor and germline sample from a patient with refractory lung adenocarcinoma who achieved marked long-term clinical benefit from anti-PD-L1 therapy. We discovered activating somatic and germline amino acid variants in JAK3 that promoted PD-L1 induction in lung cancer cells and in the tumor immune microenvironment. These findings suggest that genomic alterations that deregulate cytokine receptor signal transduction could contribute to PD-L1 activation and engagement of the PD-1 immune checkpoint in lung cancer.