Zika virus oncolytic activity requires CD8+ T cells and is boosted by immune checkpoint blockade

Abstract

Glioblastoma multiforme (GBM) is a fatal human cancer in part because GBM stem cells are resistant to therapy and recurrence is inevitable. Previously, we demonstrated Zika virus (ZIKV) targets GBM stem cells and prevents death of mice with gliomas. Here, we evaluated the immunological basis of ZIKV-mediated protection against GBM. Introduction of ZIKV into the brain tumor increases recruitment of CD8 + T and myeloid cells to the tumor microenvironment. CD8 + T cells are required for ZIKV-dependent tumor clearance, as survival benefits are lost with CD8 + T cell depletion. Moreover, while anti-PD1 antibody therapy alone moderately improves tumor survival, when co-administered with ZIKV, survival increases. ZIKV-mediated tumor clearance also results in durable protection against syngeneic tumor re-challenge, which also depends on CD8 + T cells. To address safety concerns, we generated an immune-sensitized ZIKV strain, which is effective alone or in combination with immunotherapy. Thus, oncolytic ZIKV treatment can be leveraged by immunotherapies, which may prompt combination treatment paradigms for adult GBM patients.

Oncolytic Viro-Immunotherapy: An Emerging Option in the Treatment of Gliomas

“…Antiviral immunity, inflammation, and apoptosis of GSCs are stimulated through virus infection (158). A recent in vivo study showed that CD8+ T cells were required for ZIKV oncolytic activity and immune checkpoint inhibitors could improve the effect of OVT (159). Cytosine phosphate-guanine (CpG) recoding of Zika viral genome can reduce virus infection kinetics in nonmalignant brain cells, but retains high infectivity and oncolysis in GSCs (160).…”

Zika Virus: A New Therapeutic Candidate for Glioblastoma Treatment

“…Moreover, ZIKV modified immune profiling in treated animals, inducing a local immunological response in the tumor mass [109]. In accordance, Nair S. et al showed that ZIKV treatment induces changes in the GBM microenvironment, increasing local recruitment of CD8 + T cells and myeloid cells, and thus contributing to tumor clearance and long-term protection from recurrence [110]. Similarly, Crane AT et al showed enhanced effector/memory CD4 + T cell responses in mice after ZIKV subcutaneous injection, suggesting the use of this virus as a potential adjuvant to vaccine-based immunotherapies against GBM [111].…”

Anti-PD-1 checkpoint blockade monotherapy in the orthotopic GL261 glioma model: the devil is in the detail

“…For instance, some studies find that anti-CTLA-4 antibody monotherapy leads to 50% long-term survival of GL261-bearing mice, 78 while others show the intervention to not lead to any survival extension at all. 79 Relatedly, in the CT-2A glioma model, some researchers have observed up to 60% long-term survival following anti-PD-1 monotherapy 80 while most observe no survival benefit whatsoever. 28 , 81 We do not intend to cast doubt on the scientific practices or the honest work of our colleagues, but rather to contend that common and innocuous variations in the execution of a simple experiment can lead to drastically different conclusions.…”