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

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 MongaMunir R. Tanas, David K. Meyerholz, Benjamin W. Darbro, Rebecca D. Dodd, Dawn E. Quelle

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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 ofMPNST 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.

Original languageEnglish
Pages (from-to)3484-3497
Number of pages14
JournalClinical Cancer Research
Volume29
Issue number17
DOIs
StatePublished - Sep 1 2023

Fingerprint

Dive into the research topics of 'CDK4/6-MEK Inhibition in MPNSTs Causes Plasma Cell Infiltration, Sensitization to PD-L1 Blockade, and Tumor Regression'. Together they form a unique fingerprint.

Cite this