Volume 3 Supplement 2
Intratumoral IL-15 potentiates radiation-induced anti-tumor immunity
© Pilones et al. 2015
Published: 4 November 2015
Radiotherapy (RT) can induce T cell-mediated anti-tumor immune responses by multiple mechanisms but is often unable to overcome immunosuppression in the tumor microenvironment. 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. The benefits of high dose IL-2, however, are undermined by serious toxicity and by regulatory T cell (Treg) stimulation. In contrast, IL-15 is well-tolerated and lacks Treg stimulatory activity, making it an attractive candidate for testing in combination with RT. Here we tested the hypothesis that IL-15 strengthens the pro-immunogenic effect of local RT to potentiate a durable anti-tumor immune response.
The poorly immunogenic mouse TSA breast cancer cells were implanted s.c. in syngeneic BALB/c mice and randomly assigned to one of 4 treatment groups when tumors reached 5mm average diameters: control, RT, IL-15 or RT+IL-15. RT was delivered locally in 8 Gy fractions on days 13, 14 and 15. IL-15 (2 μg/mouse) was administered s.c. peritumorally daily for 10 days starting on day 12. Mice were followed for tumor growth. A parallel experiment was done to characterize tumor-infiltrating lymphocytes (TILs) at the end of treatment (day 22).
Low dose IL-15 given peritumorally as a monotherapy induced marginal tumor growth control and had no effect on survival (median survival = 45 days compared to 76 days for control). Local RT significantly delayed tumor growth (p < 0.05 compared to control) and improved survival (median= 76 days, p < 0.05). However, highest survival advantage was seen in mice given IL-15+RT (median=102 days, p < 0.05 compared to all groups) with 1 of 6 mice showing complete tumor rejection and development of anamnestic response against tumor re-challenge. Analysis of TILs showed marked infiltration of CD8+ T cells expressing activation marker CD137 (35.3% in RT+IL-15 vs 5.9% in control, p < 0.05) while the increase was modest with either 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 rational combination of low dose intratumoral IL-15 with local RT to re-awaken immunity against poorly immunogenic tumors. 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.