Enhancement of antitumor immune response by radiation therapy combined with dual immune checkpoint inhibitor in a metastatic model of HER2-positive murine tumor

Purpose:Treatments for metastatic human epidermal growth factor receptor 2 (HER2)-positive tumors are improving but remain inadequate. We investigated activating antitumor immune response by combining radiation therapy with immune checkpoint inhibitors using mouse tumors overexpressing HER2, a pivotal driver oncogenic antigen, to develop new immunotherapies for metastatic HER2-positive tumors.Materials and methods:NT2.5 cells were inoculated into the two mammary fat pads of FVB/N mice, which were divided into four groups: no treatment (Non), anti-PD-1 and anti-CTLA4 antibodies (P1C4), irradiation of the large tumor (Rad), and combination (R + P1C4) groups. Tumor growth, immunostaining of tumor-infiltrating lymphocytes, and the proportion of HER2-tumor antigen-specific CD8-positive T cells in the spleen and tumor-infiltrating lymphocytes were analyzed.Results:In the Rad group, unirradiated and irradiated tumors shrank after treatment. Besides the directly irradiated tumors, the unirradiated tumors in the R + P1C4 group shrank the most. In the unirradiated tumors, CD8-positive T cells and FOXP3-positive T cells accumulated significantly more in the R + P1C4 group than in the P1C4 and the Rad groups (all p < 0.001). CD4-positive helper T cells accumulated significantly more in the R + P1C4 group than in the Rad group (p < 0.05), but this was not significantly different from the P1C4 group. HER2-specific CD8-positive T cells in the spleen and tumor-infiltrating lymphocytes were significantly increased in the R + P1C4 group compared to the P1C4 and Rad groups (all p < 0.0001).Conclusion:Irradiation of HER2-positive tumors induced an antitumor immune effect against the unirradiated tumor, which was enhanced by the combined use of immune checkpoint inhibitors and was mediated by enhanced recruitment of HER2-tumor antigen-specific cytotoxic T lymphocytes at the tumor site in an HER2-positive mouse tumor model. Harnessing the distant antitumor immune response induced by the combination of radiation therapy and immune checkpoint inhibitors could be a promising treatment strategy for metastatic HER2-positive tumors

MR Imaging-based Evaluation of Mesenteric Ischemia Caused by Strangulated Small Bowel Obstruction and Mesenteric Venous Occlusion: An Experimental Study Using Rabbits.

Purpose: This study assessed the MRI findings of strangulated small bowel obstruction (SBO) and mesenteric venous occlusion (MVO) in a rabbit model using 3T MRI.Materials and methods: Twenty rabbits were included in this study. The strangulated SBO and MVO models were generated via surgical procedures in nine rabbits, and sham surgery was performed in two rabbits. The success of generating the models was confirmed via angiographic, macroscopic, and microscopic findings after the surgical procedure. MRI was performed before and 30 min after inducing mesenteric ischemia. T1-weighted images (T1WIs), T2-weighted images (T2WIs), and fat-suppressed T2WIs (FS-T2WIs) were obtained using the BLADE technique, and fat-suppressed T1WIs (FS-T1WIs) were obtained. The signal intensities of the affected bowel before and after the surgical procedures were visually categorized as high, iso, and low intense compared with the findings for the normal bowel wall on all sequences. Bowel wall thickness was measured, and the signal intensity ratio (SI ratio) was calculated using the signal intensities of the bowel wall and psoas muscle.Results:Angiographic, macroscopic, and microscopic findings confirmed that all surgical procedures were successful. The ischemic bowel wall was thicker than the normal bowel. The bowel wall was thicker in the MVO model (3.17 ± 0.55 mm) than in the strangulated SBO model (2.26 ± 0.46 mm). The signal intensity and SI ratio of the bowel wall were significantly higher after the procedure than before the procedure on all sequences in both models. The mesentery adjacent to the ischemic bowel loop exhibited a high signal intensity in all animals on FS-T2WIs.Conclusion: Non-contrast MRI can be used to evaluate mesenteric ischemia caused by strangulated SBO and MVO. FS-T2WIs represented the best modality for depicting the high signal intensity in the bowel wall and mesentery caused by ischemia