| Autor: |
Le Noci V; Dipartimento di Scienze Biomediche per la Salute; Università degli Studi di Milano ; Milan, Italy., Tortoreto M; Molecular Pharmacology Unit; Fondazione IRCCS Istituto Nazionale dei Tumori ; Milan, Italy., Gulino A; Dipartimento PRO.SA.MI; Unità di Immunologia dei Tumori; Universita degli Studi di Palermo ; Palermo, Italy., Storti C; Molecular Targeting Unit; Fondazione IRCCS Istituto Nazionale dei Tumori ; Milan, Italy., Bianchi F; Dipartimento di Scienze Biomediche per la Salute; Università degli Studi di Milano ; Milan, Italy., Zaffaroni N; Molecular Pharmacology Unit; Fondazione IRCCS Istituto Nazionale dei Tumori ; Milan, Italy., Tripodo C; Dipartimento PRO.SA.MI; Unità di Immunologia dei Tumori; Universita degli Studi di Palermo ; Palermo, Italy., Tagliabue E; Molecular Targeting Unit; Fondazione IRCCS Istituto Nazionale dei Tumori ; Milan, Italy., Balsari A; Dipartimento di Scienze Biomediche per la Salute; Università degli Studi di Milano ; Milan, Italy ; Molecular Targeting Unit; Fondazione IRCCS Istituto Nazionale dei Tumori ; Milan, Italy., Sfondrini L; Dipartimento di Scienze Biomediche per la Salute; Università degli Studi di Milano ; Milan, Italy. |
| Jazyk: |
angličtina |
| Zdroj: |
Oncoimmunology [Oncoimmunology] 2015 May 27; Vol. 4 (10), pp. e1040214. Date of Electronic Publication: 2015 May 27 (Print Publication: 2015). |
| DOI: |
10.1080/2162402X.2015.1040214 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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