Radiation therapy (RT) continues to be a cornerstone in the treatment for many
cancers. Unfortunately, not all individuals respond effectively to RT resulting clinically in two groups consisting of nonresponders (progressive disease) and responders (
tumor control/cure). The mechanisms that govern the outcome of
radiotherapy are poorly understood. Interestingly, a new paradigm has emerged demonstrating that the immune system mediates many of the antitumor effects of RT. Therefore, we hypothesized that the immune response following RT may dictate the efficacy of treatment. To examine this, we developed a
tumor model that mirrors this clinically relevant phenomenon in which mice bearing Colon38, a
colon adenocarcinoma, were treated locally with 15Gy RT resulting in both nonresponders and responders. More importantly, we were able to distinguish responders from nonresponders as early as 4 days post-RT allowing for the unique opportunity to identify critical events that ultimately determined the effectiveness of
therapy. Intratumoral immune cells and
interferon-gamma were increased in responsive
tumors and licensed CD8 T cells to exhibit lytic activity against
tumor cells, a response that was diminished in
tumors refractory to RT. Combinatorial treatment with RT and the immunomodulatory
cytokine IL-12 resulted
in complete remission of
cancer in 100% of cases compared to a cure rate of only 12% with RT alone. Similar data were obtained when
IL-12 was delivered by
microspheres. Therefore, the efficacy of RT may depend on the strength of the immune response induced after
radiotherapy. Additionally,
immunotherapy that further stimulates the immune cells may enhance the effectiveness of RT.