CDK4/6-MEK Inhibition in MPNSTs Causes Plasma Cell Infiltration, Sensitization to PD-L1 Blockade, and Tumor Regression.

Abstract

PURPOSE:

Malignant peripheral nerve sheath tumors (MPNST) are lethal, Ras-driven sarcomas that lack effective therapies. We investigated effects of targeting cyclin-dependent kinases 4 and 6 (CDK4/6), MEK, and/or programmed death-ligand 1 (PD-L1) in preclinical MPNST models.

EXPERIMENTAL DESIGN:

Patient-matched MPNSTs and precursor lesions were examined by FISH, RNA sequencing, IHC, and Connectivity-Map analyses. Antitumor activity of CDK4/6 and MEK inhibitors was measured in MPNST cell lines, patient-derived xenografts (PDX), and de novo mouse MPNSTs, with the latter used to determine anti-PD-L1 response.

RESULTS:

Patient 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.

CONCLUSIONS:

CDK4/6-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.

• Authors: Jordan L Kohlmeyer, Joshua J Lingo, Courtney A Kaemmer, Amanda Scherer, Akshaya Warrier, Ellen Voigt, Juan A Raygoza Garay, Gavin R McGivney, Qierra R Brockman, Amy Tang, Ana Calizo, Kai Pollard, Xiaochun Zhang, Angela C Hirbe, Christine A Pratilas, Mariah Leidinger, Patrick Breheny, Michael S Chimenti, Jessica C Sieren, Varun Monga, Munir R Tanas, David K Meyerholz, Benjamin W Darbro, Rebecca D Dodd, Dawn E Quelle
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 29 Issue 17 Pg. 3484-3497 (09 01 2023) ISSN: 1557-3265 [Electronic] United States
• PMID: 37410426 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: ©2023 American Association for Cancer Research.

Chemical References

• CD274 protein, human
• Protein Kinase Inhibitors
• Mitogen-Activated Protein Kinase Kinases
• CDK4 protein, human
• Cyclin-Dependent Kinase 4

Topics

• Mice
• Humans
• Animals
• Neurofibrosarcoma (drug therapy)
• Plasma Cells (metabolism)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Mitogen-Activated Protein Kinase Kinases
• Cell Line, Tumor
• Tumor Microenvironment
• Cyclin-Dependent Kinase 4