- Poster presentation
- Open Access
Combination of interleukin-15 and fractionated radiotherapy for cancer treatment
© Aryankalayil et al.; licensee BioMed Central Ltd. 2014
- Published: 6 November 2014
- Tumor Growth Delay
- Activation Marker CD137
- Mouse Breast Cancer
- Immunotherapy Strategy
- Immunosuppressive Tumor
Radiotherapy (RT) can induce T cell-mediated anti-tumor immune responses by multiple mechanisms. However, due to the strongly immunosuppressive tumor microenvironment that hinders T cell function, these responses are ineffective and tumors usually escape. The common gamma-chain cytokines interleukin ( IL)-2 and IL-15 promote the proliferation of activated T cells and, therefore, are prime agents for immunotherapy strategies aimed at sustaining anti-tumor T cell responses. IL-2 at high doses is effective at inducing responses in a subset of cancer patients. However, the benefits of IL-2 are partially offset by serious toxicity and by regulatory T cell (Treg) stimulation. IL-15, on the other hand, has shown low toxicity and lacks Treg stimulatory activity, making it an attractive candidate for testing in combination with RT. Here we tested the hypothesis that IL-15 administration strengthens the pro-immunogenic effect of hypofractionated RT and contributes to inducing effective anti-tumor responses.
The poorly immunogenic TSA mouse breast cancer cells were implanted s.c. in syngeneic BALB/c mice on day 0. When tumors became palpable, mice were randomly assigned to one of 4 treatment groups (N = 4-5mice/group): control, RT, IL-15 or RT+IL-15. RT was delivered exclusively to the primary tumor in 8 Gy fractions on days 13, 14 and 15. IL-15 (5 μg/mouse) was administered i.p. or s.c. peritumorally daily for 10 days starting on day 12. Mice were followed for tumor growth or regression. In a separate experiment, mice were euthanized on day 22 to characterize tumor-infiltrating lymphocytes (TILs).
Tumor growth delay was seen when IL-15 was given peritumorally but not i.p. (p < 0.05 compared to control). Improved tumor regression was seen when RT was combined with IL-15 (p < 0.05), suggesting that IL-15 can potentiate T cell responses elicited by RT. Consistently, analysis of TILs showed a marked increase in CD8+ T cells expressing the activation marker CD137 (35.3% in RT+IL-15 versus 5.90% In control, p < 0.05) while the increase was modest with each monotherapy (18.8% in RT, 20.7% in IL-15, p < 0.05 compared to control). In addition, we found a significant increase in the ratio of effector CD4+ T-cells to Tregs (2.5 in RT+IL-15 versus 0.78 in control, p < 0.05) whereas monotherapy had no effect (1.14 in RT, 0.96 in IL-15).
Overall these results support the hypothesis that IL-15 is a valuable partner for combination treatments with local RT. We are currently elucidating the mechanisms involved in pre-clinical models in preparation for future testing in patients.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.