Radio-responsive tumors exhibit greater intratumoral immune activity than nonresponsive tumors

Abstract

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 non-responders (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 anti-tumor 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 non-responders and responders. More importantly, we were able to determine responders from non-responders as early as four days post-RT allowing for the unique opportunity to identify critical events that ultimately determined the effectiveness of therapy. Intratumoral immune cells and IFNγ 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.

Use a survival model to correlate single-nucleotide polymorphisms of DNA repair genes with radiation dose–response in patients with non-small cell lung cancer

“…1) may also include radiation damage of the immune system. Recently, it has been reported that the immune system plays an important role in controlling the tumor [27–30]. Damage of the immune system may not directly cause conventional treatment mortality, but may affect tumor control and eventually patient death due to disease progression.…”

Low stromal Foxp3+ regulatory T-cell density is associated with complete response to neoadjuvant chemoradiotherapy in rectal cancer

“…Modulation of T-cell subsets may therefore play a significant role in response to neoadjuvant CRT. Indeed, high CD3 and CD8 expression in pretreatment rectal cancer biopsy samples is associated with tumour regression following CRT ( Yasuda et al , 2011 ; Anitei et al , 2014 ), and radioresponsiveness has an immune-mediated component in animal models of colon, breast and other solid cancers ( Apetoh et al , 2007 ; Liang et al , 2013 ; Gerber et al , 2014 ). In breast cancer, the disappearance of Tregs following neoadjuvant CRT is associated with complete pathological response ( Ladoire et al , 2008 ).…”

Evaluating the impact of smoking on disease‐specific survival outcomes in patients with human papillomavirus–associated oropharyngeal cancer treated with transoral robotic surgery

“…In an animal study comparing RT responders and nonresponders, a marked difference was noted with respect to the presence of intratumoral immune cells. In responders, an enlarged, cytotoxic, CD8‐positive T‐cell population with a concomitant increase in the concentration of cytotoxic cytokine interferon‐γ clearly was demonstrated . Other studies have shown that the therapeutic effects of RT are almost completely abolished when depleting CD8‐positive T cells in mouse models .…”