PKR induces TGF-β and limits oncolytic immune therapy.

Content Provider	Europe PMC
Author	Hong, Bangxing Sahu, Upasana Mullarkey, Matthew P Hong, Evan Pei, Guangsheng Yan, Yuanqing Otani, Yoshihiro Banasavadi-Siddegowda, Yeshavanth Fan, Huihui Zhao, Zhongming Yu, Jianhua Caligiuri, Michael A Kaur, Balveen
Copyright Year	2023
Abstract	BackgroundMammalian cells have developed multiple intracellular mechanisms to defend against viral infections. These include RNA-activated protein kinase (PKR), cyclic GMP-AMP synthase and stimulation of interferon genes (cGAS-STING) and toll-like receptor-myeloid differentiation primary response 88 (TLR-MyD88). Among these, we identified that PKR presents the most formidable barrier to oncolytic herpes simplex virus (oHSV) replication in vitro.MethodsTo elucidate the impact of PKR on host responses to oncolytic therapy, we generated a novel oncolytic virus (oHSV-shPKR) which disables tumor intrinsic PKR signaling in infected tumor cells.ResultsAs anticipated, oHSV-shPKR resulted in suppression of innate antiviral immunity and improves virus spread and tumor cell lysis both in vitro and in vivo. Single cell RNA sequencing combined with cell-cell communication analysis uncovered a strong correlation between PKR activation and transforming growth factor beta (TGF-ß) immune suppressive signaling in both human and preclinical models. Using a murine PKR targeting oHSV, we found that in immune-competent mice this virus could rewire the tumor immune microenvironment to increase the activation of antigen presentation and enhance tumor antigen-specific CD8 T cell expansion and activity. Further, a single intratumoral injection of oHSV-shPKR significantly improved the survival of mice bearing orthotopic glioblastoma. To our knowledge, this is the first report to identify dual and opposing roles of PKR wherein PKR activates antivirus innate immunity and induces TGF-ß signaling to inhibit antitumor adaptive immune responses.ConclusionsThus, PKR represents the Achilles heel of oHSV therapy, restricting both viral replication and antitumor immunity, and an oncolytic virus that can target this pathway significantly improves response to virotherapy.
Volume Number	11
PubMed Central reference number	PMC9936322
Issue Number	2
PubMed reference number	36796878
Journal	Journal for Immunotherapy of Cancer [J Immunother Cancer]
e-ISSN	20511426
DOI	10.1136/jitc-2022-006164
Language	English
Publisher	BMJ Publishing Group
Publisher Date	2023-02-01
Publisher Place	BMA House, Tavistock Square, London, WC1H 9JR
Access Restriction	Open
Rights License	This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/. © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Subject Keyword	Oncolytic Virotherapy Oncolytic Viruses Brain Neoplasms Adaptive Immunity Antigen Presentation
Content Type	Text
Resource Type	Article
Subject	Immunology Pharmacology Immunology and Allergy Oncology Cancer Research Molecular Medicine