Melanoma Cell Intrinsic GABA(A) Receptor Enhancement Potentiates Radiation and Immune Checkpoint Inhibitor Response by Promoting Direct and T Cell-Mediated Antitumor Activity

• Type of Material: Article
• Authors: Daniel Pomeranz Krummel, Emory University; Tahseen H Nasti, Emory University; Milota Kaluzova, Emory University; Laura Kallay, University of Cincinnati; Debanjan Bhattacharya, University of Cincinnati; Johannes C Melms, Columbia Univ Coll Phys & Surg; DAP Krummel, University of Cincinnati; Benjamin Izar, Columbia University College of Physicians and Surgeons, New York; Maxwell Xu, Johns Hopkins University; Andre Burnham, Emory University; Taukir Ahmed, Univ. of Wisconsin-Milwaukee; Guanguan Li, Univ. of Wisconsin-Milwaukee; David Lawson, Emory University; Jeanne Kowalski, Emory University; Yichun Cao, Emory University; Jeffrey Switchenko, Emory University; Dan Ionascu, University of Cincinnati; James M Cook, Univ Wisconsin; Mario Medvedovic, University of Cincinnati; Andrew Jenkins, Emory University; Mohammad Khan, Emory University; Soma Sengupta, Emory University
• Language: English
• Date: 2021-02-18
• Publisher: ELSEVIER SCIENCE INC
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ijrobp.2020.10.025
• Title of Journal or Parent Work: INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
• Volume: 109
• Issue: 4
• Start Page: 1040
• End Page: 1053
• Keywords: Oncology; MB; SURVIVAL; MUTATIONS; IPILIMUMAB; OPEN-LABEL; Radiology, Nuclear Medicine & Medical Imaging; MULTICENTER; Science & Technology; BRAIN METASTASES; METASTATIC MELANOMA; COMBINED NIVOLUMAB; Life Sciences & Biomedicine; DABRAFENIB

Abstract

Purpose: Most patients with metastatic melanoma show variable responses to radiation therapy and do not benefit from immune checkpoint inhibitors. Improved strategies for combination therapy that leverage potential benefits from radiation therapy and immune checkpoint inhibitors are critical. Methods and Materials: We analyzed metastatic melanoma tumors in the TCGA cohort for expression of genes coding for subunits of type A γ-aminobutyric acid (GABA) receptor (GABAAR), a chloride ion channel and major inhibitory neurotransmitter receptor. Electrophysiology was used to determine whether melanoma cells possess intrinsic GABAAR activity. Melanoma cell viability studies were conducted to test whether enhancing GABAAR mediated chloride transport using benzodiazepine-impaired viability. A syngeneic melanoma mouse model was used to assay the effect of benzodiazepine on tumor volume and its ability to potentiate radiation therapy or immunotherapy. Treated tumors were analyzed for changes in gene expression by RNA sequencing and presence of tumor-infiltrating lymphocytes by flow cytometry. Results: Genes coding for subunits of GABAARs express functional GABAARs in melanoma cells. By enhancing GABAAR-mediated anion transport, benzodiazepines depolarize melanoma cells and impair their viability. In vivo, benzodiazepine alone reduces tumor growth and potentiates radiation therapy and α-PD-L1 antitumor activity. The combination of benzodiazepine, radiation therapy, and α-PD-L1 results in near complete regression of treated tumors and a potent abscopal effect, mediated by increased infiltration of polyfunctional CD8+ T cells. Treated tumors show expression of cytokine–cytokine receptor interactions and overrepresentation of p53 signaling. Conclusions: This study identifies an antitumor strategy combining radiation and/or an immune checkpoint inhibitor with modulation of GABAARs in melanoma using benzodiazepine.