Journal article
CDK4/6-MEK inhibition in MPNSTs causes plasma cell infiltration, sensitization to PD-L1 blockade, and tumor regression
Clinical cancer research, Vol.29(17), pp.3484-3497
09/01/2023
DOI: 10.1158/1078-0432.CCR-23-0749
PMCID: PMC10528807
PMID: 37410426
Abstract
PURPOSEMalignant peripheral nerve sheath tumors (MPNSTs) are lethal, Ras-driven sarcomas that lack effective therapies. We investigated effects of targeting CDK4/6, MEK, and/or programmed death-ligand 1 (PD-L1) in preclinical MPNST models. EXPERIMENTAL DESIGNPatient-matched MPNSTs and precursor lesions were examined by FISH, RNAseq, IHC, and Connectivity-Map analyses. Antitumor activity of CDK4/6 and MEK inhibitors was measured in MPNST cell lines, patient-derived xenografts (PDXs), and de novo mouse MPNSTs, with the latter used to determine anti-PD-L1 response. RESULTSPatient tumor analyses identified CDK4/6 and MEK as actionable targets for MPNST therapy. Low-dose combinations of CDK4/6 and MEK inhibitors synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death, and decreased clonogenic survival of MPNST cells. In immune-deficient mice, dual CDK4/6-MEK inhibition slowed tumor growth in 4 of 5 MPNST PDXs. In immunocompetent mice, combination therapy of de novo MPNSTs caused tumor regression, delayed resistant tumor outgrowth, and improved survival relative to monotherapies. Drug-sensitive tumors that regressed contained plasma cells and increased cytotoxic T cells, whereas drug-resistant tumors adopted an immunosuppressive microenvironment with elevated MHC II-low macrophages and increased tumor cell PD-L1 expression. Excitingly, CDK4/6-MEK inhibition sensitized MPNSTs to anti-PD-L1 immune checkpoint blockade (ICB) with some mice showing complete tumor regression. CONCLUSIONSCDK4/6-MEK inhibition induces a novel plasma cell-associated immune response and extended antitumor activity in MPNSTs, which dramatically enhances anti-PD-L1 therapy. These preclinical findings provide strong rationale for clinical translation of CDK4/6-MEK-ICB targeted therapies in MPNST as they may yield sustained antitumor responses and improved patient outcomes.
Details
- Title: Subtitle
- CDK4/6-MEK inhibition in MPNSTs causes plasma cell infiltration, sensitization to PD-L1 blockade, and tumor regression
- Creators
- Jordan L Kohlmeyer - University of IowaJoshua J Lingo - University of IowaCourtney A Kaemmer - University of IowaAmanda Scherer - University of IowaAkshaya Warrier - University of IowaEllen Voigt - Sanford ResearchJuan A Raygoza GarayGavin R McGivney - University of IowaQierra R Brockman - University of IowaAmy Tang - Eastern Virginia Medical SchoolAna Calizo - Johns Hopkins UniversityKai Pollard - Sidney Kimmel Comprehensive Cancer CenterXiaochun Zhang - Washington University in St. LouisAngela C Hirbe - Washington University in St. LouisChristine A Pratilas - Sidney Kimmel Comprehensive Cancer CenterMariah Leidinger - University of IowaPatrick Breheny - University of IowaMichael S Chimenti - University of Iowa Hospitals and ClinicsJessica C Sieren - University of IowaVarun Monga - University of IowaMunir R Tanas - University of IowaDavid K Meyerholz - University of IowaBenjamin W Darbro - University of IowaRebecca D Dodd - University of IowaDawn E Quelle - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.29(17), pp.3484-3497
- DOI
- 10.1158/1078-0432.CCR-23-0749
- PMID
- 37410426
- PMCID
- PMC10528807
- NLM abbreviation
- Clin Cancer Res
- eISSN
- 1557-3265
- Grant note
- name: National Cancer Institute, award: P30 CA086862; DOI: 10.13039/100000065, name: National Institute of Neurological Disorders and Stroke, award: R01 NS119322; DOI: 10.13039/100001545, name: Children's Tumor Foundation, award: Young Investigator Award; DOI: 10.13039/100000057, name: National Institute of General Medical Sciences, award: GM067795; name: NF1 Research Initiative, award: n/a
- Language
- English
- Electronic publication date
- 07/06/2023
- Date published
- 09/01/2023
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Microbiology and Immunology; Hematology, Oncology, and Blood & Marrow Transplantation; Stead Family Department of Pediatrics; Pathology; Biostatistics; Medical Genetics and Genomics; Neuroscience and Pharmacology; Holden Comprehensive Cancer Center; Internal Medicine; Iowa Institute of Human Genetics
- Record Identifier
- 9984442227202771
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