Abstract

BACKGROUND: In-situ tumor ablation provides the immune system with the appropriate antigens to induce anti-tumor immunity. Here, we present an innovative technique for generating anti-tumor immunity by delivering exogenous ultra-high concentration (>10,000ppm) gaseous nitric oxide (UHCgNO) intratumorally.METHODS: The capability of UHCgNO to induce apoptosis was tested in vitro in mouse colon (CT26), breast (4T1) and Lewis lung carcinoma (LLC-1) cancer cell lines. In vivo, UHCgNO was studied by treating CT26 tumor-bearing mice in-situ and assessing the immune response using a Challenge assay.RESULTS: Exposing CT26, 4T1 and LLC-1 cell lines to UHCgNO for 10s-2.5min induced cellular apoptosis 24h after exposure. Treating CT26 tumors in-situ with UHCgNO followed by surgical resection 14days later resulted in a significant secondary anti-tumor effect in vivo. 100% of tumor-bearing mice treated with 50,000ppm UHCgNO and 64% of mice treated with 20,000ppm UHCgNO rejected a second tumor inoculation, compared to 0% in the naive control for 70days. Additionally, more dendrocytes infiltrated the tumor 14days post UHCgNO treatment versus the nitrogen control. Moreover, T-cell penetration into the primary tumor was observed in a dose-dependent manner. Systemic increases in T- and B-cells were seen in UHCgNO-treated mice compared to nitrogen control. Furthermore, polymorphonuclear-myeloid-derived suppressor cells were downregulated in the spleen in the UHCgNO-treated groups.CONCLUSIONS: Taken together, our data demonstrate that UHCgNO followed by the surgical removal of the primary tumor 14days later induces a strong and potent anti-tumor response.

View details for DOI 10.1186/s12935-022-02828-z

View details for PubMedID 36514083