Recombinant virus-like particles presenting IL-33 successfully modify the tumor microenvironment and facilitate antitumor immunity in a model of breast cancer

Abstract

Recently, interleukin (IL)-33 has been closely associated with a variety of clinical cancers. IL-33 presents both protumorigenic, and less frequently, antitumorigenic functions depending on disease conditions. IL-33 signaling appears to be a possible target for the treatment of applicable tumor diseases. This study aimed to develop an effective approach to intervene in IL-33 functioning in tumors and reveal the immunotherapeutic potential of anti-IL-33 active immunization. Recombinant truncated hepatitis B virus core antigen (HBcAg), presenting mature IL-33 molecules on the surface of virus-like particles (VLPs), was prepared and used to immunize BALB/c mice in a model of murine 4T1 breast cancer. The immunization was performed through either a preventive or therapeutic strategy in two separate studies. Anti-IL-33 immunization with VLPs elicited a persistent and highly titrated specific antibody response and significantly suppressed orthotopic tumor growth in the preventive study and lung metastasis in both studies. The underlying mechanisms might include promoting tumor-specific Th1 and CTL-mediated cellular responses and the expression of the effector molecule interferon-γ (IFN-γ), suppressing T-helper type 2 (Th2) responses, and significantly reducing the infiltration of immunosuppressive Treg (regulatory T) cells and myeloid-derived suppressor cells (MDSCs) into tumor tissues in the immunized mice. In conclusion, anti-IL-33 active immunization employing recombinant VLPs as an antigen delivery platform effectively modified the tumor microenvironment and promoted antitumor immunity, indicating the potential of this approach as a new and promising immunotherapeutic strategy for the treatment of cancers where IL-33 plays a definite protumorigenic role. STATEMENT OF SIGNIFICANCE: Interleukin (IL)-33 is closely associated with a variety of clinical cancers. IL-33 signaling appears to be a possible target for the treatment of applicable tumor diseases. Recombinant truncated hepatitis B virus core antigen (HBcAg), presenting mature IL-33 molecules on the surface of virus-like particles (VLPs), was prepared and used to immunize BALB/c mice in a model of murine 4T1 breast cancer. The immunization was performed through either a preventive or therapeutic strategy in two separate studies. Anti-IL-33 immunization with VLPs elicited a persistent and highly titrated specific antibody response and significantly suppressed orthotopic tumor growth and lung metastasis in both studies. Furthermore, anti-IL-33 active immunization employing recombinant VLPs as an antigen delivery platform effectively modified the tumor microenvironment and promoted antitumor immunity, indicating its potential as a new and promising immunotherapeutic strategy for the treatment of cancers where IL-33 plays a definite protumorigenic role.

Keywords: Anti-cytokine active immunization; Interleukin (IL)-33; Tumor; Virus-like particle (VLP).