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Autor(en) / Beteiligte

Titel

In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras -Mutant Lung Adenocarcinoma

Ist Teil von

Ort / Verlag

United States

Erscheinungsjahr

2020

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

Despite substantial progress in lung cancer immunotherapy, the overall response rate in patients with -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 CRISPR screen in a / LUAD model. Our data showed that loss of the histone chaperone in tumor cells sensitizes tumors to anti-PD-1 treatment. Mechanistic studies revealed that tumor cell-intrinsic 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 epigenetic CRISPR screen, we identified as a critical regulator of LUAD sensitivity to anti-PD-1 therapy. 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. . .

Sprache: Englisch
Identifikatoren: ISSN: 2159-8274
eISSN: 2159-8290
DOI: 10.1158/2159-8290.cd-19-0780
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7007372

Format: –
Schlagworte: Adenocarcinoma of Lung - drug therapy, Adenocarcinoma of Lung - genetics, Adenocarcinoma of Lung - immunology, Adenocarcinoma of Lung - pathology, Animals, Cell Cycle Proteins - genetics, Cell Cycle Proteins - metabolism, Cell Differentiation - drug effects, Cell Differentiation - genetics, Cell Line, Tumor, CRISPR-Cas Systems - genetics, Disease Models, Animal, Drug Resistance, Neoplasm - genetics, Epigenesis, Genetic - immunology, Gene Expression Regulation, Neoplastic - immunology, Gene Knockout Techniques, HEK293 Cells, Humans, Immune Checkpoint Inhibitors - pharmacology, Immune Checkpoint Inhibitors - therapeutic use, Lung - pathology, Lung Neoplasms - drug therapy, Lung Neoplasms - genetics, Lung Neoplasms - immunology, Lung Neoplasms - pathology, Macrophages - drug effects, Macrophages - immunology, Macrophages - metabolism, Male, Mice, Molecular Chaperones - genetics, Molecular Chaperones - metabolism, Programmed Cell Death 1 Receptor - antagonists & inhibitors, Programmed Cell Death 1 Receptor - immunology, Proto-Oncogene Proteins p21(ras) - genetics, RNA, Guide, CRISPR-Cas Systems - genetics, RNA, Small Interfering - metabolism, RNA-Seq, Tumor Microenvironment - drug effects, Tumor Microenvironment - immunology, Tumor Suppressor Protein p53 - genetics

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