Abstract
Stereotactic body radiotherapy (SBRT) is known to induce important immunologic changes within the tumor microenvironment (TME). However, little is known regarding the early immune responses within the TME in the first few weeks following SBRT. Therefore, we used the canine spontaneous tumor model to investigate TME responses to SBRT, and how local injection of immune modulatory antibodies to OX40 and TLR 3/9 agonists might modify those responses. Pet dogs with spontaneous cancers (melanoma, carcinoma, sarcoma, n = 6 per group) were randomized to treatment with either SBRT or SBRT combined with local immunotherapy. Serial tumor biopsies and serum samples were analyzed for immunologic responses. SBRT alone resulted at two weeks after treatment in increased tumor densities of CD3+ T cells, FoxP3+ Tregs, and CD204+ macrophages, and increased expression of genes associated with immunosuppression. The addition of OX40/TLR3/9 immunotherapy to SBRT resulted in local depletion of Tregs and tumor macrophages and reduced Treg-associated gene expression (FoxP3), suppressed macrophage-associated gene expression (IL-8), and suppressed exhausted T cell-associated gene expression (CTLA4). Increased concentrations of IL-7, IL-15, and IL-18 were observed in serum of animals treated with SBRT and immunotherapy, compared to animals treated with SBRT. A paradoxical decrease in the density of effector CD3+ T cells was observed in tumor tissues that received combined SBRT and immunotherapy as compared to animals treated with SBRT only. In summary, these results obtained in a spontaneous large animal cancer model indicate that addition of OX40/TLR immunotherapy to SBRT modifies important immunological effects both locally and systemically.
Highlights
Radiotherapy (RT) can serve as an immune stimulus, as various activated immune cells are recruited to the tumor microenvironment following radiation exposure [1,2]
Tumors treated with Stereotactic body radiotherapy (SBRT) alone had increased expression of IL-8, while this effect was reduced in tumors treated with SBRT + immunotherapy
We evaluated the immunologic effects of SBRT in spontaneous canine tumors, as well as the impact of in situ vaccination with OX40/TLR3/9 immunotherapy
Summary
Radiotherapy (RT) can serve as an immune stimulus, as various activated immune cells are recruited to the tumor microenvironment following radiation exposure [1,2]. Another proposed mechanism of OX40 immunotherapy is inhibition of the generation and function of regulatory T cells (Tregs) and subsequent removal of the Treg immune suppressive effects within the TME [23–28] It has been demonstrated in in vitro and in vivo preclinical models that radiation induces OX40 ligand expression, leading to expansion of costimulatory signaling through OX40 on T cells [29–32]. High-dose radiation in combination with a TLR9 agonist in pre-clinical tumor models enhanced anti-tumor immune responses via increasing activated CD4+ and CD8+ T cells within the tumor microenvironment [34]. Building upon these prior findings, we hypothesized that the immunostimulatory effects of SBRT with in situ tumor vaccination would enhance anti-tumor immune responses compared to SBRT alone.
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