ABSTRACT
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.
Subject(s)
Cyclin-Dependent Kinases/antagonists & inhibitors , Cyclin-Dependent Kinases/genetics , Genomic Instability , Lung Neoplasms/genetics , Small Cell Lung Carcinoma/genetics , Animals , Antineoplastic Agents/pharmacology , CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Chemokine CXCL9/metabolism , DNA Damage , Female , Humans , Immune System , Inflammation , Interferon-gamma/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/immunology , Male , Mice , Micronucleus Tests , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Pyrazoles/pharmacology , Pyrroles/pharmacology , Signal Transduction , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/immunology , Tumor Necrosis Factor-alpha/metabolism , Cyclin-Dependent Kinase-Activating KinaseABSTRACT
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.
Subject(s)
Adenocarcinoma of Lung/drug therapy , Cell Cycle Proteins/metabolism , Drug Resistance, Neoplasm/genetics , Immune Checkpoint Inhibitors/pharmacology , Lung Neoplasms/drug therapy , Molecular Chaperones/metabolism , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/immunology , Adenocarcinoma of Lung/pathology , Animals , CRISPR-Cas Systems/genetics , Cell Cycle Proteins/genetics , Cell Differentiation/drug effects , Cell Differentiation/genetics , Cell Line, Tumor , Disease Models, Animal , Epigenesis, Genetic/immunology , Gene Expression Regulation, Neoplastic/immunology , Gene Knockout Techniques , HEK293 Cells , Humans , Immune Checkpoint Inhibitors/therapeutic use , Lung/pathology , Lung Neoplasms/genetics , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Macrophages/drug effects , Macrophages/immunology , Macrophages/metabolism , Male , Mice , Molecular Chaperones/genetics , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Proto-Oncogene Proteins p21(ras)/genetics , RNA, Guide, Kinetoplastida/genetics , RNA, Small Interfering/metabolism , RNA-Seq , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Tumor Suppressor Protein p53/geneticsABSTRACT
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.
