Synergistic antitumor immune response mediated by paclitaxel-conjugated nanohybrid oncolytic adenovirus with dendritic cell therapy

Front Immunol. 2024 May 21:15:1355566. doi: 10.3389/fimmu.2024.1355566. eCollection 2024.

Abstract

Dendritic cell (DC)-based vaccines have emerged as a promising strategy in cancer immunotherapy due to low toxicity. However, the therapeutic efficacy of DC as a monotherapy is insufficient due to highly immunosuppressive tumor environment. To address these limitations of DC as immunotherapeutic agent, we have developed a polymeric nanocomplex incorporating (1) oncolytic adenovirus (oAd) co-expressing interleukin (IL)-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF) and (2) arginine-grafted bioreducible polymer with PEGylated paclitaxel (APP) to restore antitumor immune surveillance function in tumor milieu and potentiate immunostimulatory attributes of DC vaccine. Nanohybrid complex (oAd/APP) in combination with DC (oAd/APP+DC) induced superior expression level of antitumor cytokines (IL-12, GM-CSF, and interferon gamma) than either oAd/APP or DC monotherapy in tumor tissues, thus resulting in superior intratumoral infiltration of both endogenous and exogenous DCs. Furthermore, oAd/APP+DC treatment led superior migration of DC to secondary lymphoid organs, such as draining lymph nodes and spleen, in comparison with either monotherapy. Superior migration profile of DCs in oAd/APP+DC treatment group resulted in more prolific activation of tumor-specific T cells in these lymphoid organs and greater intratumoral infiltration of T cells. Additionally, oAd/APP+DC treatment led to lower subset of tumor infiltrating lymphocytes and splenocytes being immunosuppressive regulatory T cells than any other treatment groups. Collectively, oAd/APP+DC led to superior induction of antitumor immune response and amelioration of immunosuppressive tumor microenvironment to elicit potent tumor growth inhibition than either monotherapy.

Keywords: DC; T cells; Treg; antitumor immune response; nanohybrid; oncolytic Ad; therapeutic vaccine.

MeSH terms

  • Adenoviridae* / genetics
  • Animals
  • Cancer Vaccines / immunology
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Dendritic Cells* / immunology
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Humans
  • Immunotherapy / methods
  • Mice
  • Mice, Inbred C57BL
  • Oncolytic Virotherapy* / methods
  • Oncolytic Viruses* / genetics
  • Oncolytic Viruses* / immunology
  • Paclitaxel* / pharmacology
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology

Substances

  • Paclitaxel
  • Cancer Vaccines
  • Granulocyte-Macrophage Colony-Stimulating Factor

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from the National Research Foundation of Korea (2021R1A2C301016611, 2023R1A2C1004062, C-OY.; 2022R1I1A1A01071162, 2023R1A2C1003830, A-RY).