Radiotherapy is enhanced by CPH:SA IL-1α microparticles in a murine HNSCC tumor model.

Abstract

Background: Radiotherapy (RT) can trigger immunogenic cell death which may be exploited to improve the effectiveness of immunotherapy. However, recent results from clinical trials testing RT/immunotherapy combinations in head and neck squamous cell carcinoma patients (HNSCC) have been disappointing. Interleukin-1 alpha (IL-1α) is a cytokine that can activate various aspects of anti-tumor immunity including dendritic cell (DC) activation which is critical for the recruitment of tumor infiltrating lymphocytes. Here we test the cytokine IL-1α encapsulated in 20:80 1,6-bis-(p-carboxyphenoxy)-hexane:sebacic acid (CPH:SA) copolymer-based microparticles (IL-1αMPs) as an adjuvant to RT in a murine syngeneic HNSCC mouse model. Thus the main research objective of this current study was to evaluate if IL-1αMPs can enhance the antitumor immune response of radiotherapy.

Methods: Activation of immune cells in response to RT ± human recombinant IL-1α was evaluated in human peripheral blood mononuclear cell (PBMC):cancer cell co-cultures. A bilateral HNSCC tumor syngeneic mouse model was used to monitor mEERL tumor growth and immune cell recruitment in response to RT (8 Gy to irradiated tumor only) with and without intraperitoneal delivery of IL-1αMPs.  RESULTS: Results showed that IL-1α induced the activation of monocytes, NK cells, T cells, and DCs in PBMC:Cal-27 cell co-cultures but there was no enhanced immune cell activation (with the exception of NK cells) in vitro when combined with RT. RT and RT + IL-1αMPs significantly suppressed growth in irradiated mEERL tumors compared to control. However, only the combination therapy was able to slowdown growth of the non-irradiated tumors compared to the other treatment groups. Immune cell profiling revealed that RT caused acute lymphodepletion on treatment day 3 which was reversed by treatment day 11 in RT-exposed mice. The anti-tumor effect of RT + IL-1α was accompanied by significantly increased infiltration of DCs in the irradiated tumor and increased CD8 + and antigen (E7)-specific CD8 + T cell infiltration in both irradiated and non-irradiated tumors. The anti-tumor response of the combination therapy was completely abrogated by CD8 + T cell depletion.

Conclusions: This data suggests that the addition of CPH:SA IL-1αMPs to RT may boost anti-tumor immune response and target both local and systemic disease. This combination is worthy of further investigation as an immunotherapeutic strategy and could represent a promising approach to improve survival outcomes in HNSCC patients.