Harnessing the Activation of RIG-I Like Receptors to Inhibit Glioblastoma Tumorigenesis.

Francesca Bufalieri,Lucia Di Marcotullio,Paola Infante,Irene Basili

doi:10.3389/fnmol.2021.710171

Abstract

Glioblastoma (GB) is an incurable form of brain malignancy in an adult with a median survival of less than 15 months. The current standard of care, which consists of surgical resection, radiotherapy, and chemotherapy with temozolomide, has been unsuccessful due to an extensive inter- and intra-tumoral genetic and molecular heterogeneity. This aspect represents a serious obstacle for developing alternative therapeutic options for GB. In the last years, immunotherapy has emerged as an effective treatment for a wide range of cancers and several trials have evaluated its effects in GB patients. Unfortunately, clinical outcomes were disappointing particularly because of the presence of tumor immunosuppressive microenvironment. Recently, anti-cancer approaches aimed to improve the expression and the activity of RIG-I-like receptors (RLRs) have emerged. These innovative therapeutic strategies attempt to stimulate both innate and adaptive immune responses against tumor antigens and to promote the apoptosis of cancer cells. Indeed, RLRs are important mediators of the innate immune system by triggering the type I interferon (IFN) response upon recognition of immunostimulatory RNAs. In this mini-review, we discuss the functions of RLRs family members in the control of immune response and we focus on the potential clinical application of RLRs agonists as a promising strategy for GB therapy.

Highlights

Glioblastoma (GB) is the most frequent and aggressive primary adult brain tumor, with a median overall survival (OS) of approximately 1 year (Ostrom et al, 2014)
Multiple genetic drivers are involved in the onset of GB, including amplification of epidermal growth factor receptor (EGFR) gene and mutations in telomerase reverse transcriptase (TERT), isocitrate dehydrogenase (IDH), phosphatase and tensin homolog (PTEN), platelet-derived growth factor receptor alpha (PDGFRα), and neurofibromatosis type 1 (NF1) genes (Stoyanov and Dzhenkov, 2018)
P(I:C-LC) has been used as a tumor peptidebased vaccine adjuvant in low-grade glioma patients achieving promising results (Okada et al, 2015). These findings suggest the potential of integrating radiotherapy and/or chemotherapy and immunotherapy based on the activation of Retinoic acid-inducible gene I (RIG-I) for the development of new clinical perspectives for GB therapy

Summary

INTRODUCTION

Glioblastoma (GB) is the most frequent and aggressive primary adult brain tumor, with a median overall survival (OS) of approximately 1 year (Ostrom et al, 2014). First-line therapy for newly diagnosed GB consists of maximal surgical resection of the tumor, followed by radiotherapy (RT) and concomitant adjuvant chemotherapy with the alkylating agent Temozolomide (TMZ; Stupp et al, 2005, 2009). The disease remains incurable and often returns as recurrent GB (Lieberman, 2017). Limited progress in the development of more effective therapeutic approaches for GB is mostly due to its heterogeneous genetic, molecular landscape, and cell plasticity (Brennan et al, 2013; Meyer et al, 2015; Gangoso et al, 2021)

RLRs Agonists for Glioblastoma Therapy

BRIEF OVERVIEW OF IMMUNOTHERAPEUTIC APPROACHES IN GLIOBLASTOMA

AGONISTS OF RLRs AS A PROMISING THERAPEUTIC STRATEGY FOR GLIOBLASTOMA

CONCLUSION