Abstract A02: MEK-CDK4/6 inhibition induces plasma cell tumor infiltration and sensitizes de novo MPNSTs to immune checkpoint blockade


 Malignant peripheral nerve sheath tumors (MPNSTs) are deadly, Ras-driven sarcomas that lack effective therapies. Many tumors are unresectable and toxic chemotherapies are ineffectual. The sensitivity of MPNSTs to immune checkpoint blockade (ICB) therapies is not known, although sarcomas are generally unresponsive. Patient tumor analyses comparing MPNSTs to benign precursors identified Ras effectors, MEK and CDK4/6 kinases, as rational targets for therapy. We tested the efficacy of dual MEK-CDK4/6 inhibition versus single drug therapy using preclinical MPNST models. In MPNST cells, low-dose drug combinations synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death and decreased clonogenic survival. In de novo MPNSTs in immune competent mice, combination therapy caused tumors to shrink, substantially delayed resistant tumor outgrowth and improved survival relative to monotherapies. Tumor regression was associated with an immune activation gene expression profile featuring plasma cell infiltration, an event not previously observed with MEK-CDK4/6 inhibitor therapy. In other human tumor types, intratumoral plasma cells prognose better overall survival and improved response to ICB therapies. Excitingly, MEK-CDK4/6 therapy sensitized de novo MPNSTs to anti-programmed death ligand 1 (PD-L1) therapy with the combination achieving complete tumor ablation and apparent cure in 10% of mice. These findings implicate a critical role for plasma cells in mediating MPNST regression in response to kinase inhibitor therapy and sensitizing tumors to PD-L1 targeting. This novel therapeutic combination is a promising option for MPNST therapy that could improve ICB efficacy in other solid tumors.
 Citation Format: Joshua Lingo, Jordan Kohlmeyer, Courtney Kaemmer, Amanda Scherer, Ellen Voigt, Michael Chimenti, Munir Tanas, Varun Monga, Ben Darbro, David Meyerholz, Rebecca Dodd, Dawn Quelle. MEK-CDK4/6 inhibition induces plasma cell tumor infiltration and sensitizes de novo MPNSTs to immune checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A02.