Tumor-Associated Macrophages/Microglia in Glioblastoma Oncolytic Virotherapy: A Double-Edged Sword

Abstract

Oncolytic virotherapy is a rapidly progressing field that uses oncolytic viruses (OVs) to selectively infect malignant cells and cause an antitumor response through direct oncolysis and stimulation of the immune system. Despite demonstrated pre-clinical efficacy of OVs in many cancer types and some favorable clinical results in glioblastoma (GBM) trials, durable increases in overall survival have remained elusive. Recent evidence has emerged that tumor-associated macrophage/microglia (TAM) involvement is likely an important factor contributing to OV treatment failure. It is prudent to note that the relationship between TAMs and OV therapy failures is complex. Canonically activated TAMs (i.e., M1) drive an antitumor response while also inhibiting OV replication and spread. Meanwhile, M2 activated TAMs facilitate an immunosuppressive microenvironment thereby indirectly promoting tumor growth. In this focused review, we discuss the complicated interplay between TAMs and OV therapies in GBM. We review past studies that aimed to maximize effectiveness through immune system modulation-both immunostimulatory and immunosuppressant-and suggest future directions to maximize OV efficacy.

Keywords: glioblastoma (GBM); oncolytic virotherapy; tumor microenvironment; tumor-associated macrophages/microglia (TAMs).

Figure 1

Schematic representation of the interaction between M1/M2 tumor-associated macrophage/microglia (TAM) polarization with oncolytic viral distribution and tumor growth in glioblastoma multiforme. Elements of the microenvironment influence polarization between TAM subsets of immuno-suppressive M2 and immune-stimulatory M1. Tumors polarize TAMs towards the M2 phenotype, which support tumor growth. Oncolytic virotherapy (OV) inhibits tumor growth through two main mechanisms: direct oncolysis and the antitumor response. The latter is a result of virus-induced polarization towards the M1 phenotype, which creates an immune response against tumor growth. However, this also stimulates an antiviral response, limiting the beneficial effects of OVs. IL interleukin, M-CSF macrophage colony stimulating factor, TGF-β transforming growth factor beta, PGE2 prostaglandin E2, IFN-γ interferon gamma, LPS lipopolysaccharide, Th T helper, Treg T regulatory, VEGF vascular endothelial growth factor, CD cluster of differentiation, PD-L1 programmed cell death ligand 1, and TNF-α tumor necrosis factor alpha.