Abstract
BackgroundThe mechanisms by which vaccinia virus (VACV) interacts with the innate immune components are complex and involve different mechanisms. iNOS-mediated NO production by myeloid cells is one of the central antiviral mechanisms and this study aims to investigate specifically whether iNOS-mediated NO production by myeloid cells, is involved in tumor eradication following the virus treatment.MethodsHuman colon adenocarcinoma (HCT-116) xenograft tumors were infected by VACV. Infiltration of iNOS+ myeloid cell population into the tumor, and virus titer was monitored following the treatment. Single-cell suspensions were stained for qualitative and quantitative flow analysis. The effect of different myeloid cell subsets on tumor growth and colonization were investigated by depletion studies. Finally, in vitro culture experiments were carried out to study NO production and tumor cell killing. Student’s t test was used for comparison between groups in all of the experiments.ResultsInfection of human colon adenocarcinoma (HCT-116) xenograft tumors by VACV has led to recruitment of many CD11b+ ly6G+ myeloid-derived suppressor cells (MDSCs), with enhanced iNOS expression in the tumors, and to an increased intratumoral virus titer between days 7 and 10 post-VACV therapy. In parallel, both single and multiple rounds of iNOS-producing cell depletions caused very rapid tumor growth within the same period after virus injection, indicating that VACV-induced iNOS+ MDSCs could be an important antitumor effector component. A continuous blockade of iNOS by its specific inhibitor, L-NIL, showed similar tumor growth enhancement 7–10 days post-infection. Finally, spleen-derived iNOS+ MDSCs isolated from virus-injected tumor bearing mice produced higher amounts of NO and effectively killed HCT-116 cells in in vitro transwell experiments.ConclusionsWe initially hypothesized that NO could be one of the factors that limits active spreading of the virus in the cancerous tissue. In contrast to our initial hypothesis, we observed that PMN-MDSCs were the main producer of NO through iNOS and NO provided a beneficial antitumor effect, The results strongly support an important novel role for VACV infection in the tumor microenvironment. VACV convert tumor-promoting MDSCs into tumor-killing cells by inducing higher NO production.
Highlights
The mechanisms by which vaccinia virus (VACV) interacts with the innate immune components are complex and involve different mechanisms. inducible nitric oxide synthase (iNOS)-mediated NO production by myeloid cells is one of the central antiviral mechanisms and this study aims to investigate whether iNOS-mediated NO production by myeloid cells, is involved in tumor eradication following the virus treatment
We recently reported that colonization of human colorectal cancer xenografts with the oncolytic VACV strain GLV-1h68 in nude mice, is followed by significant upregulation of murine proinflammatory cytokines and chemokines such as interferon-gamma (IFNγ), IFNγ-induced protein 10 (IP-10), monocyte chemoattractant protein (MCP)-1/3/5, macrophage inflammatory protein 1 (MIP-1), regulated on activation normal T cell expressed and secreted (RANTES), IL-6, IL-1b and tumor necrosis factors (TNF-α), as well as infiltration of F4/80low CXCR4+ myeloid cells [22]
Combination treatment resulted in the same kinetics; it is interesting to note that this group recruited the highest amount of intratumoral iNOS+ PMN-myeloid-derived suppressor cells (MDSCs) on day 14, which correlated with slightly improved tumor regression
Summary
The mechanisms by which vaccinia virus (VACV) interacts with the innate immune components are complex and involve different mechanisms. iNOS-mediated NO production by myeloid cells is one of the central antiviral mechanisms and this study aims to investigate whether iNOS-mediated NO production by myeloid cells, is involved in tumor eradication following the virus treatment. The mechanisms by which vaccinia virus (VACV) interacts with the innate immune components may play a decisive role in its antitumor activity by tilting the immune response from viral clearance to tumor elimination. Tumor-targeting mechanisms of VACV include virus-mediated direct oncolysis, antivascular effects and induction of antitumor immune responses [3,4,5]. The latter mechanism of action might be essential in the elimination of tumor cells which are able to escape virus infection [6]. The three critical stages to ensure the effectiveness of any oncolytic virus therapy include: efficient virus targeting to tumor sites, fast and continuous virus replication in tumor cells, and resistance to the host antiviral immunity. An important question that remains to be answered is whether the host immune system, adept at controlling viral infections, would have an impact on the tumor
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