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.
Highlights
Once in the tumor cells, Oncolytic viruses (OVs) work through a mixed mechanism of induction of oncolysis and stimulation of antitumor immune activity [1,8]
Immune cell evasion is a classic characteristic of GBM [30], and OVs aim to reverse this by exposing the tumor to the innate and adaptive immune system
tumor-associated macrophage/microglia (TAM) are recruited to the tumor microenvironment (TME) by chemoattractants from glioma cells, such as CC chemokine ligand 2 (CCL2)[53,54] and soluble colony-stimulating factor 1 [55,56]
Summary
Oncolytic virotherapy centers on engineered viruses that target neoplastic cells. Oncolytic viruses (OVs) have shown great promise in the treatment of various cancer types due to their selective replication in cancer cells and the subsequent induction of tumor cell death [1,2]. HSV an attractive OV candidate for many reasons, including a large and highly stable genome, its potent cytolytic capability, high immunogenicity, and a convenient genome for genetic engineering; the availability of effective anti-herpetic drugs to treat adverse reactions is an added benefit [16,19]. Another common virus studied for glioma virotherapy is poliovirus. Adenovirus can function as a nonintegrating vector with relatively high capacity for gene delivery, including delivery of suicide genes [24–27] It demonstrated successful induction of immune responses in GBM and caused direct oncolysis and autophagy [28]. Immune cell evasion is a classic characteristic of GBM [30], and OVs aim to reverse this by exposing the tumor to the innate and adaptive immune system
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