Radiation and DMXAA limit tumour development in a urethane-induced lung cancer model through inflammatory response


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Kay Shigemori, Yanyan Jiang, Stephen Stribbling, Jennifer C. Martin, Luiza H.M. Lourenco, Anderson J. Ryan

Abstract

Background

Carcinogen-induced lung cancer in A/J mice is a well-established model of tumour initiation and development. The impact of radiation and cGAS-STING activation on promoting tumour development in this model is not well understood. In this study, we examined the effect of radiation and the STING agonist, DMXAA (5,6-dimethylxanthenone-4-acetic acid), on the development of urethane-induced lung cancer.

Method

Female A/J mice were treated with urethane (5%, i.p.) to induce the development of lung tumours. Three days after urethane treatment, mice received whole thorax-irradiation (13 Gy) followed 4 h later by DMXAA (15 mg/kg i.p) and were sacrificed after 5 months to assess tumour development. Control groups received whole-thorax irradiation, DMXAA, or urethane alone. Superficial lung tumours were counted at the end of the study and lungs and spleens were collected for histology and molecular analyses. 

Results

The number of superficial lung tumours was significantly lower in the radiation-treated group compared with the urethane-treated control (p<0.01) whereas DMXAA treatment alone did not significantly reduce tumour counts. Radiation combined with DMXAA significantly decreased tumour counts compared with radiation alone (p<0.01). Lung sections from the radiation and radiation plus DMXAA combination groups showed clusters of CD45+ cells (10-40% of which are CD3+ T-cells), apparent throughout the tissue, while these were not seen in mice treated with urethane or DMXAA treatments alone. An increase in relative spleen weights was seen in both the irradiated (+19.9%) and DMXAA combination (+23.1%) groups compared with urethane-treated controls. 

Conclusion

Surprisingly, radiation treatment inhibited the development of tumours in urethane treated A/J mice, and this effect was augmented in combination with the STING agonist, DMXAA.

Impact statement

These initial findings may have future implications for strategies for the early treatment of lung and other cancers, and they further suggest that inflammatory/immune responses, including modulation of the STING pathway, may be an important aspect of early tumour development that could be targeted therapeutically.