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Abstract
Cancer immunotherapy has encountered many difficulties in the face of the expectation to eradicate cancer, and new breakthroughs are required. We have previously shown that UV-inactivated Sendai virus particles (hemagglutinating virus of Japan envelope; HVJ-E) induce immunity against multiple tumor types. In this study, a novel pseudovirion that stimulates more robust antitumor immunity was designed for cancer treatment. First, we found that culturing murine splenocytes with HVJ-E in combination with interleukin (IL)-12 resulted in a remarkable increase in IFN-γ production compared with that observed in splenocytes cultured with IL-12 alone. The synergistic effects of HVJ-E and IL-12 on IFN-γ production were caused by viral F proteins independently of HVJ-E fusion activity and not by hemagglutination from hemagglutinin-neuraminidase (HN) proteins. We next constructed HN-depleted HVJ-E expressing the Fc region of immunoglobulin G (IgG) on the envelope and single-chain IL-12 containing the ZZ domain of protein A to produce an IL-12-conjugated HVJ-E particle without hemagglutinating activity. IL-12-conjugated HVJ-E dramatically enhanced the amount of IFN-γ produced by immune cells. Intratumoral injection of IL-12-conjugated HVJ-E eradicated murine melanomas more effectively than injection of wild-type HVJ-E through increased production of melanoma-specific CTLs. IL-12-conjugated HVJ-E preferentially accumulated in the lungs after systemic administration. When small metastatic melanoma foci were formed in the lungs, systemic administration of IL-12-conjugated HVJ-E significantly reduced the number of metastatic foci by inducing local production of IFN-γ in the lungs and generating large numbers of melanoma-specific CTLs. IL-12-conjugated HVJ-E is a promising tool for the treatment of cancers, including lung metastasis.
Highlights
Cancer tissues use several systems to induce immunotolerance, including the activation of FoxP3þCD4þCD25þ regulatory T cells (Treg; ref. 1)
IL-12–conjugated HVJ-E dramatically enhanced the amount of IFN-g produced by immune cells
When small metastatic melanoma foci were formed in the lungs, systemic administration of IL-12–conjugated HVJ-E significantly reduced the number of metastatic foci by inducing local production of IFN-g in the lungs and generating large numbers of melanoma-specific CTLs
Summary
Cancer tissues use several systems to induce immunotolerance, including the activation of FoxP3þCD4þCD25þ regulatory T cells (Treg; ref. 1). Cancer tissues use several systems to induce immunotolerance, including the activation of FoxP3þCD4þCD25þ regulatory T cells Much attention has been paid to cancer immunotherapy because it may suppress tumor metastasis and recurrence by activating immune cells to target cancer cells. Provenge induces the activation of effector lymphocytes specific for cancer cells, and ipilimumab (anti-CTLA4 antibody) and the anti-PD1 antibody inhibit the downregulation of effector lymphocyte activity; these systems have shown beneficial effects for the treatment of cancer [2,3,4,5,6]. More effective immunotherapy should result from the activation of cancer-targeting effector lymphocytes and the suppression of immunosuppressive factors [7,8,9]
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