Inactivated Sendai Virus Particles Eradicate Tumors by Inducing Immune Responses through Blocking Regulatory T Cells

Abstract

UV-inactivated, replication-defective Sendai virus particles [hemagglutinating virus of Japan envelope (HVJ-E)] injected into murine colon carcinoma (CT26) tumors growing in syngeneic BALB/c mice eradicated 60% to 80% of the tumors and obviously inhibited the growth of the remainder. Induced adaptive antitumor immune responses were dominant in the tumor eradication process because the effect was abrogated in severe combined immunodeficient mice. Murine and human dendritic cells underwent dose-dependent maturation by HVJ-E in vitro. Profiles of cytokines secreted by dendritic cells after HVJ-E stimulation showed that the amount of interleukin-6 (IL-6) released was comparable to that elicited by live HVJ. + regulatory T cell (Treg)-mediated suppression and IL-6 was presumably dominant for this phenomenon. We also confirmed such rescue in mice treated with HVJ-E in vivo. Moreover, antitumor effect of HVJ-E was significantly reduced by an in vivo blockade of IL-6 signaling. This is the first report to show that HVJ-E alone can eradicate tumors and the mechanism through which it induces antitumor immune responses. Because it can enhance antitumor immunity and simultaneously remove Treg-mediated suppression, HVJ-E shows promise as a novel therapeutic for cancer immunotherapy.

Efficient eradication of hormone‐resistant human prostate cancers by inactivated Sendai virus particle

“…39 We have previously reported that HVJ-E also induces Type I IFN secretion in murine DCs in a fusion-dependent manner, 40 but not in murine cancer cells. 27,28 However, in the culture medium of PC3 cells, significant induction of IFN-a and -b was detected following HVJ-E treatment (Fig. 4a).…”

“…[26][27][28] It induces tumor-specific NK cell migration through CXCL10 production by DCs, and enhances NK cell activity through the secretion of IFN from DCs. 28 HVJ-E also enhances DC maturation and activates CTLs against cancer cells by enhancing effector T cells and suppressing regulatory T cells.…”

“…26 We have previously demonstrated that HVJ-E can eradicate mouse tumors, such as colon cancer (CT26) and renal cancer (Renca), by activating dendritic cells (DC). 27,28 Following HVJ-E treatment, DCs secrete various cytokines and chemokines, such as Type I IFN, IL-6 and CXCL10, resulting in the activation of cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. 27,28 IFN-a and -b have generated a lot of interest as anti-viral and anti-tumor cytokines.…”

“…27,28 Following HVJ-E treatment, DCs secrete various cytokines and chemokines, such as Type I IFN, IL-6 and CXCL10, resulting in the activation of cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. 27,28 IFN-a and -b have generated a lot of interest as anti-viral and anti-tumor cytokines. 29 However, Type I IFN was not produced in mouse tumor cells following HVJ-E treatment, and HVJ-E failed to directly kill mouse tumor cells in the absence of DCs.…”

Gene therapy progress and prospects cancer: oncolytic viruses

“…Intratumoral administration of UV-inactivated, replication-deficient Sendai virus induced a robust antitumoral immune response (including cytotoxic T lymphocyte (CTL) induction, dendritic cell maturation and antagonism of Tregs) and resulted in significant efficacy in CT26 syngeneic murine colorectal cancer model. 48 It will be interesting to study how much of this vaccine effect contributes to antitumoral efficacy in oncolytic Sendai virus studies. A 'vaccine' effect was also seen with parvovirus H-1 in a rat lung tumor metastases model.…”