Anti-tumor activity of CpG-ODN aerosol in mouse lung metastases
Lucia Sfondrini1, Michele Sommariva, Monica Tortoreto
1Dipartimento di Scienze Biomediche per Salute, Università degli Studi di Milano, Milan, Italy. lucia.sfondrini@unimi.it
Abstract:
Studies in preclinical models have demonstrated the superior anti-tumor effect of CpG oligodeoxynucleotides (CpG-ODN) when administered at the tumor site rather than systemically. We evaluated the effect of aerosolized CpG-ODN on lung metastases in mice injected with immunogenic N202.1A mammary carcinoma cells or weakly immunogenic B16 melanoma cells. Upon reaching the bronchoalveolar space, aerosolized CpG-ODN activated a local immune response, as indicated by production of IL-12p40, IFN-γ and IL-1β and by recruitment and maturation of DC cells in bronchoalveolar lavage fluid of mice. Treatment with aerosolized CpG-ODN induced an expansion of CD4+ cells in lung and was more efficacious than systemic i.p. administration against experimental lung metastases of immunogenic N202.1A mammary carcinoma cells, whereas only i.p. delivery of CpG-ODN provided anti-tumor activity, which correlated with NK cell expansion in the lung, against lung metastases of the poorly immunogenic B16 melanoma. The inefficacy of aerosol therapy to induce NK expansion was related to the presence of immunosuppressive macrophages in B16 tumor-bearing lungs, as mice depleted of these cells by clodronate treatment responded to aerosol CpG-ODN through expansion of the NK cell population and significantly reduced numbers of lung metastases. Our results indicate that tumor immunogenicity and the tumor-induced immunosuppressive environment are critical factors to the success of CpG therapy in the lung, and point to the value of routine sampling of the lung immune environment in defining an optimal immunotherapeutic strategy.
Insights
Aerosolized CpG oligodeoxynucleotides (CpG-ODN) effectively treat lung tumors by activating local immunity, but efficacy depends on tumor type and the lung
Area of Science:
- Immunology
- Cancer Research
- Pulmonary Medicine
Background:
- Preclinical studies show intratumoral CpG oligodeoxynucleotides (CpG-ODN) are superior to systemic administration for anti-tumor effects.
- Lung metastases present a challenge for localized immunotherapy due to the unique pulmonary immune environment.
Purpose of the Study:
- To evaluate the efficacy of aerosolized CpG-ODN in treating lung metastases from immunogenic and weakly immunogenic tumors in mice.
- To investigate the immune mechanisms underlying the differential response to aerosolized CpG-ODN therapy.
Main Methods:
- Mice bearing lung metastases of N202.1A mammary carcinoma (immunogenic) or B16 melanoma (weakly immunogenic) were treated with aerosolized or systemic CpG-ODN.
- Immune responses were assessed by measuring cytokine production (IL-12p40, IFN-γ, IL-1β), immune cell populations (DC, CD4+, NK cells), and tumor burden.
- Immunosuppressive macrophages were depleted using clodronate to assess their role in treatment resistance.
Main Results:
- Aerosolized CpG-ODN induced local immune responses, including IL-12p40, IFN-γ, IL-1β production and DC maturation in the lungs.
- Aerosolized CpG-ODN was more effective than systemic delivery against immunogenic N202.1A tumors, promoting CD4+ T cell expansion.
- Systemic CpG-ODN, but not aerosolized, showed efficacy against weakly immunogenic B16 melanoma, correlating with NK cell expansion.
- Depletion of immunosuppressive macrophages in B16 melanoma-bearing lungs restored NK cell expansion and response to aerosolized CpG-ODN.
Conclusions:
- Tumor immunogenicity and the presence of immunosuppressive lung macrophages critically influence the success of aerosolized CpG-ODN immunotherapy.
- Aerosol delivery of CpG-ODN can be an effective strategy for lung metastases, particularly for immunogenic tumors.
- Assessing the lung immune microenvironment is crucial for optimizing immunotherapeutic strategies against lung cancer.
