Pre-Clinical Studies

Radiation Therapy Induces DNA Sensing and Immunomodulation In Vivo

Radiation therapy (RT) is one of three core modalities used to treat cancer, although tumor recurrence is observed even with high doses of fractionated stereotactic ablative radiotherapy (SAbR). Recent studies have revealed that RT-induced tumor cell death is “immunogenic” because it acts like “in situ” vaccination and triggers an antitumor immune response, including cytotoxic T lymphocytes (CTLs), the main effectors against tumor cells. The potential combination of immunotherapy and RT is based on its well-known immunogenic properties. Because RT is targeted directly to the tumor, it does not inherently have an immune-compromising effect on the host.

Sterile inflammation occurs after tissue damage in the absence of pathogens. The hallmark of sterile inflammation is the rapid infiltration of neutrophils, as observed in the spleen, thymus, and gut after whole-body ionizing radiation in mice. Inflammatory responses are triggered by damage-associated molecular patterns (DAMPs), which are released from cells dying from exposure to RT. A previous study from our lab revealed that sterile inflammation caused by RT involves tumor-associated neutrophils (TAN) that induce tumor cell killing mediated by reactive oxygen species and, eventually, by the involvement of tumor-infiltrating CTLs.

DNA sensing as a part of DAMPs is an important aspect of RT-mediated immune response. One of our ongoing projects aims at [1] investigating the involvement of RT-induced DNA sensing in RT-induced tumor neutrophilic infiltration (RT-N); [2] gaining insights into the mechanisms of enhanced DNA sensing by RT-Ns and [3] modulating RT-N to enhance DNA-sensing mediated tumor suppressive effect.

Our findings from ongoing and future experiments will provide valuable insights into the DNA-sensing pathways activated by RT, the tumor microenvironment, and radiation therapy’s interaction with the immune system for better therapeutic intervention in patients with cancer.