Immunologic Effects of Stereotactic Body Radiotherapy in Dogs with Spontaneous Tumors and the Impact of Intratumoral OX40/TLR Agonist Immunotherapy

被引:11
作者
Boss, Mary-Keara [1 ]
Watts, Remy [2 ]
Harrison, Lauren G. [1 ]
Hopkins, Sophie [3 ]
Chow, Lyndah [3 ]
Trageser, Erin [1 ]
Easton, Carina [4 ]
LaRue, Susan M. [1 ]
Regan, Daniel [4 ]
Dewhirst, Mark W. [5 ]
Dow, Steven [3 ]
机构
[1] Colorado State Univ, Dept Environm Hlth & Radiol Sci, Ft Collins, CO 80523 USA
[2] Atlantic Vet Coll, Dept Compan Anim, Charlottetown, PE C1A 4P3, Canada
[3] Colorado State Univ, Dept Clin Sci, Ft Collins, CO 80523 USA
[4] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA
[5] Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC 27710 USA
关键词
dog; cancer; T cells; cytokines; Toll-like receptor; macrophage; RADIATION-THERAPY; ANTITUMOR IMMUNITY; TOXICITY CRITERIA; CANCER; CELLS; COMBINATION; ENGAGEMENT; DOCETAXEL; PHENOTYPE; NIVOLUMAB;
D O I
10.3390/ijms23020826
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页数:17
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