Introduction: Metastases are responsible for a major portion of the morbidity and mortality of cancer, accounting for approximately 90% of all cancer-related deaths. In situ destruction of the tumor mass has been reported to provide the immune system with an antigen source for the induction of antitumor immunity, which can destroy distant metastases. One of the proposed mechanisms involves the induction of antigen presenting cells that may result in the stimulation of adaptive immunity. Our research group is developing an innovative gaseous Nitric Oxide (gNO) based tumor ablation method. NO is a short-lived free radical which, at high doses, possesses anticancer properties. Moreover, NO has been proven to activate innate and adaptive responses of the immune system against tumors. Previous in vivo results showed that all gNO-treated colon tumor-bearing (CT26 model) mice (n=6) were resistant to a secondary CT26 cell inoculation. In the current study, high dose gNO has been used to destroy breast and lung solid tumors in mice. The immune response stimulated following this treatment was tested.
Materials and Methods: Breast and lung tumor-bearing mice (4T1 and LLC1 models, respectively) were treated with 50,000 ppm gNO intratumorally. A metastasis model was induced in all gas-treated tumor bearing mice up to 14 days post treatment by challenging the mice with a second cancer cell inoculation (challenge assay). Naïve mice, inoculated with the same cancer cells, served as an internal control. Results: All gNO-treated lung tumor-bearing mice (n=2) were resistant to a second LLC1 lung cancer cell inoculation as compared to 100% tumor take in the control group (n=3, p = 0.03). In gNO-treated breast tumor-bearing mice (n=3), using the highly aggressive 4T1 model that mimics human stage 4 breast cancer, an inhibition in a secondary 4T1 tumor take was observed as compared to the tumor take in the control group (n=3). All naïve mice that were inoculated with 4T1 cells developed a tumor after 5 days, while no gNO-treated 4T1 tumor-bearing mice developed a 4T1 challenge tumor at this time point (p =0.01). At 7 days after 4T1 challenge cell inoculation 1 of 3 mice developed a challenge tumor (p =0.08).
Conclusion: The proposed project represents development of a novel treatment for cancer. Our innovative gNO based treatment may serve to treat lethal solid tumors locally and their distant metastases systemically via the stimulation of an anti-tumor immune response.
Citation Format: Hila Confino, Shay Yarkoni, Matan Goldshtein, Elya Dekel, Omer Lerner, Shani Puyesky, Steve Lisi, Rinat Kalaora, Pam Golden, Amir Avniel, Prof. Ido Wolf. Nitric oxide tumor ablation stimulates an anti-tumor immune response in mice [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO072.