Poly(I: C) and CpG-ODN combined aerosolization to treat lung metastases and counter the immunosuppressive microenvironment

Valentino Le Noci, Monica Tortoreto, Alessandro Gulino, Chiara Storti, Francesca Bianchi, Nadia Zaffaroni, Claudio Tripodo, Elda Tagliabue, Andrea Balsari, Lucia Sfondrini

Research output: Contribution to journalArticle

Abstract

The immunostimulatory ability of synthetic oligonucleotides containing CpG motifs (CpG-ODN), agonists of Toll-like receptor 9 (TLR9), can be harnessed to promote antitumor immunity by their application at the tumor site to stimulate local activation of innate immunity; however, particularly in the lung, tumor-associated immunosuppression can subvert such antitumor innate immune responses. To locally maintain continuous activation of innate subpopulations while inhibiting immunosuppressive cells, we evaluated aerosol delivery CpG-ODN combined with Poly(I:C), a TLR3 agonist able to convert tumor-supporting macrophages to tumoricidal effectors, in the treatment of B16 melanoma lung metastases in C57BL/6 mice. Aerosolization of CpG-ODN with Poly(I:C) into the bronchoalveolar space reduced the presence of M2-associated arginase- and IL-10-secreting macrophages in tumor-bearing lungs and increased the antitumor activity of aerosolized CpG-ODN alone against B16 lung metastases without apparent signs of toxicity or injury of the bronchial-bronchiolar structures and alveolar walls. Moreover, CpG-ODN/Poly(I:C) aerosol combined with dacarbazine, a therapeutic agent used in patients with inoperable metastatic melanoma able to exert immunostimulatory effects, led to a significant increase in antitumor activity as compared to treatments with aerosolized CpG-ODN/Poly(I:C) or dacarbazine alone. This effect was related to an enhanced recruitment and cytotoxic activity of tumor-infiltrating NK cells in the lung. Our results point to aerosol delivery as a convenient approach for repeated applications of immunostimulants in patients with lung metastases to maintain a continuous local activation of innate immune cells while suppressing polarization of tumor-infiltrating macrophages to an M2 phenotype.

Original languageEnglish
JournalOncoImmunology
Volume4
Issue number10
DOIs
Publication statusPublished - Oct 3 2015

Keywords

  • aerosol delivery
  • dacarbazin
  • lung metastases
  • mice
  • TLR agonists

ASJC Scopus subject areas

  • Immunology and Allergy
  • Oncology
  • Immunology

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