Dataset Information

IFN-? mediates the antitumor effects of radiation therapy in a murine colon tumor.

ABSTRACT: Cancer treatments using ionizing radiation (IR) therapy are thought to act primarily through the induction of tumor cell damage at a molecular level. However, a new concept has recently emerged, suggesting that the immune system is required for effective IR therapy. Our work here has identified interferon gamma (IFN-?) as an essential cytokine for the efficacy of IR therapy. Local IR (15 Gy) to mice bearing Colon38, a colon adenocarcinoma, decreases tumor burden in wild-type animals. Interestingly, IR therapy had no effect on tumor burden in IFN?KO mice. We further determined that intratumoral levels of IFN-? increased 2 days following IR, which directly correlated with a decrease in tumor burden that was not a result of direct cytotoxic effects of IFN-? on tumor cells. T cells from IR-treated tumors exhibited a far greater capacity to lyse tumor cells in a (51)Cr release assay, a process that was dependent on IFN-?. CD8(+) T cells were the predominant producers of IFN-?, as demonstrated by IFN-? intracellular staining and studies in IFN-? reporter mice. Elimination of CD8(+) T cells by antibody treatment reduced the intratumoral levels of IFN-? by over 90%. More importantly, elimination of CD8(+) T cells completely abrogated the effects of radiation therapy. Our data suggest that IFN-? plays a pivotal role in mediating the antitumor effects of IR therapy.

SUBMITTER: Gerber SA

PROVIDER: S-EPMC3668027 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

IFN-γ mediates the antitumor effects of radiation therapy in a murine colon tumor.

Gerber Scott A SA Sedlacek Abigail L AL Cron Kyle R KR Murphy Shawn P SP Frelinger John G JG Lord Edith M EM

The American journal of pathology 20130412 6

Cancer treatments using ionizing radiation (IR) therapy are thought to act primarily through the induction of tumor cell damage at a molecular level. However, a new concept has recently emerged, suggesting that the immune system is required for effective IR therapy. Our work here has identified interferon gamma (IFN-γ) as an essential cytokine for the efficacy of IR therapy. Local IR (15 Gy) to mice bearing Colon38, a colon adenocarcinoma, decreases tumor burden in wild-type animals. Interesting ...[more]

PMID: 23583648

Similar Datasets

Project description:Although remarkable preclinical antitumor effects have been shown for tumor necrosis factor-? (TNF) alone and combined with radiation, its clinical use has been hindered by systemic dose-limiting toxicities. We investigated the physiological and antitumor effects of radiation therapy combined with the novel nanomedicine CYT-6091, a 27-nm average-diameter polyethylene glycol-TNF-coated gold nanoparticle, which recently passed through phase 1 trials.The physiologic and antitumor effects of single and fractionated radiation combined with CYT-6091 were studied in the murine 4T1 breast carcinoma and SCCVII head and neck tumor squamous cell carcinoma models.In the 4T1 murine breast tumor model, we observed a significant reduction in the tumor interstitial fluid pressure (IFP) 24 hours after CYT-6091 alone and combined with a radiation dose of 12 Gy (P<.05 vs control). In contrast, radiation alone (12 Gy) had a negligible effect on the IFP. In the SCCVII head and neck tumor model, the baseline IFP was not markedly elevated, and little additional change occurred in the IFP after single-dose radiation or combined therapy (P>.05 vs control) despite extensive vascular damage observed. The IFP reduction in the 4T1 model was also associated with marked vascular damage and extravasation of red blood cells into the tumor interstitium. A sustained reduction in tumor cell density was observed in the combined therapy group compared with all other groups (P<.05). Finally, we observed a more than twofold delay in tumor growth when CYT-6091 was combined with a single 20-Gy radiation dose-notably, irrespective of the treatment sequence. Moreover, when hypofractionated radiation (12 Gy × 3) was applied with CYT-6091 treatment, a more than five-fold growth delay was observed in the combined treatment group of both tumor models and determined to be synergistic.Our results have demonstrated that TNF-labeled gold nanoparticles combined with single or fractionated high-dose radiation therapy is effective in reducing IFP and tumor growth and shows promise for clinical translation.

Project description:BackgroundRadiation therapy (RT) elicits DNA double-strand breaks, resulting in tumor cytotoxicity and a type I interferon (IFN) response via stimulator of interferon genes (STING) activation. We investigated whether combining RT with an ataxia-telangiectasia mutated inhibitor promoted these effects and amplified tumor immunity.MethodsMice-bearing syngeneic flank tumors (MOC2 head and neck squamous cell carcinoma or B78 melanoma) were treated with tumor-directed RT and oral administration of AZD0156. Specific immune cell depletion, type 1 interferon receptor 1 knock-out mice (IFNAR1-KO), and STING-deficient tumor cells were used to investigate tumor-immune crosstalk following RT and AZD0156 treatment.ResultsCombining RT and AZD0156 reduced tumor growth compared with RT or AZD0156 alone in mice bearing MOC2 or B78 tumors. Low-dose AZD0156 (1-100 nM) alone did not affect tumor cell proliferation but suppressed tumor cell clonogenicity in combination with RT. Low-dose AZD0156 with RT synergistically increased IFN-β, major histocompatibility complex (MHC)-I, and programmed death-ligand 1 (PD-L1) expression in tumor cells. In contrast to wild-type mice, IFNAR1-KO mice showed reduced CD8+T cell tumor infiltration and poor survival following RT+AZD0156 treatment. CD8+T cell depletion reduced antitumor response during RT+AZD0156 treatment. STING-deficient MOC2 (MOC2-STING+/-) or B78 (B78-STING-/-) tumors eliminated the effects of RT+AZD0156 on the expression of IFN-β, MHC-I, and PD-L1, and reduced CD8+T cell infiltration and migration. Additional anti-PD-L1 therapy promoted antitumor response by elevation of tumor-MHC-I and lymphocyte activation.ConclusionsCombined radiation and AZD0156 increase STING-dependent antitumor response. Tumor-derived cell-autonomous IFN-β amplification drives both MHC-I and PD-L1 induction at the tumor cell surface, which is required by anti-PD-L1 therapy to promote antitumor immune response following RT and AZD0156 combination therapy.

Project description:PurposeInternal organ motion reduces the accuracy and efficacy of radiation therapy. However, there is a lack of tools to objectively (based on a medical or scientific task) assess the dosimetric consequences of motion, especially on an individual basis. We propose to use therapy operating characteristic (TOC) analysis to quantify the effects of motion on treatment efficacy for individual patients. We demonstrate the application of this tool with pancreatic stereotactic body radiation therapy (SBRT) clinical data and explore the origin of motion sensitivity.MethodsThe technique is described as follows. (a) Use tumor-motion data measured from patients to calculate the motion-convolved dose of the gross tumor volume (GTV) and the organs at risk (OARs). (b) Calculate tumor control probability (TCP) and normal tissue complication probability (NTCP) from the motion-convolved dose-volume histograms. (c) Construct TOC curves from TCP and NTCP models. (d) Calculate the area under the TOC curve (AUTOC) and use it as a figure of merit for treatment efficacy. We used tumor motion data measured from patients to calculate the relation between AUTOC and motion magnitude for 25 pancreatic SBRT treatment plans. Furthermore, to explore the driving factor of motion sensitivity of a given plan, we compared the dose distribution of motion-sensitive plans and motion-robust plans and studied the dependence of motion sensitivity to motion directions.ResultsOur technique is able to recognize treatment plans that are sensitive to motion. Under the presence of motion, the treatment efficacy of some plans changes from providing high tumor control and low risks of complications to providing no tumor control and high risks of side effects. Several treatment plans experience falloffs in AUTOC at a smaller magnitude of motion than other plans. In our dataset, a potential indicator of a motion-sensitive treatment plan is that the duodenum is in proximity to the tumor in the SI direction.ConclusionsThe TOC framework can serve as a tool to quantify the effects of internal organ motion in radiation therapy. With pancreatic SBRT clinical data, we applied this tool to study the change in treatment efficacy induced by motion for individual treatment plans. This framework could potentially be used clinically to understand the effects of motion in an individual patient and to design a patient-specific motion management plan. This framework could also be used in research to evaluate different components of the treatment process, such as motion-management techniques, treatment-planning algorithms, and treatment margins.

Dataset Information

IFN-? mediates the antitumor effects of radiation therapy in a murine colon tumor.

Publications

IFN-γ mediates the antitumor effects of radiation therapy in a murine colon tumor.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets