Abstract
Vaccinia virus (VACV) is a double-stranded DNA virus that devotes a large portion of its 200 kbp genome to suppressing and manipulating the immune response of its host. Here, we investigated how targeted removal of immunomodulatory genes from the VACV genome impacted immune cells in the tumor microenvironment with the intention of improving the therapeutic efficacy of VACV in breast cancer. We performed a head-to-head comparison of six mutant oncolytic VACVs, each harboring deletions in genes that modulate different cellular pathways, such as nucleotide metabolism, apoptosis, inflammation, and chemokine and interferon signaling. We found that even minor changes to the VACV genome can impact the immune cell compartment in the tumor microenvironment. Viral genome modifications had the capacity to alter lymphocytic and myeloid cell compositions in tumors and spleens, PD-1 expression, and the percentages of virus-targeted and tumor-targeted CD8+ T cells. We observed that while some gene deletions improved responses in the nonimmunogenic 4T1 tumor model, very little therapeutic improvement was seen in the immunogenic HER2/neu TuBo model with the various genome modifications. We observed that the most promising candidate genes for deletion were those that interfere with interferon signaling. Collectively, this research helped focus attention on the pathways that modulate the immune response in the context of VACV oncolytic virotherapy. They also suggest that the greatest benefits to be obtained with these treatments may not always be seen in "hot tumors."
Highlights
Oncolytic viruses preferentially infect and kill cancer cells while promoting antitumor immunity, classifying them as a form of immunotherapy [1]
Mutation of Vaccinia virus (VACV) immunomodulatory genes Previous studies have identified that deletion of VACV F1L, K7R, N1L, C6L, A41L, and B8R plus B18R genes enhance immune responses to recombinant vaccine vectors in vivo
Growth properties of mutant VACV in vitro When we examined the relationship between virus amplification in vitro and cell killing over 72 hours, most of the mutations had little effect on either phenotype when compared to the DJ2R virus (Fig. 1B and C)
Summary
Oncolytic viruses preferentially infect and kill cancer cells while promoting antitumor immunity, classifying them as a form of immunotherapy [1]. The FDA's approval of talimogene laherparepvec (TVEC) in 2016 increased confidence in this growing field of immunotherapy; oncolytic viruses have not yielded the same type of clinical success as other immunotherapeutic approaches [1]. VACV has many attributes that make it a suitable cancer therapeutic, including a large coding capacity for transgenes, easy manipulation, a good safety profile, and the inability to integrate into the host genome [2]. VACVs are in clinical trials [2], and there is continuing research aimed at improving the long lasting antitumor immunity, by encoding cytokines like GMCSF or IL2 into the virus genome [3, 4].
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