Combining immunotherapy with high-dose radiation therapy (HDRT) significantly inhibits tumor growth in a syngeneic mouse model of high-risk neuroblastoma

• Published in: Heliyon Vol. 9; no. 6; p. e17399
• Main Authors: Boboila, Shuobo, Okochi, Shunpei, Banerjee, Debarshi, Barton, Sunjay, Street, Cherease, Zenilman, Ariela L., Wang, Qi, Gartrell, Robyn D., Saenger, Yvonne M., Welch, David, Wu, Cheng-Chia, Kadenhe-Chiweshe, Angela, Yamashiro, Darrell J., Connolly, Eileen P.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2023; Elsevier
• Subjects: Cancer therapeutics; Combination therapy; High dose radiation therapy; Immunotherapy; MYCN-amplified neuroblastoma; Neuroblastoma; Novel syngeneic mouse model; MYCN-amplified neuroblastoma; Cancer therapeutics; Novel syngeneic mouse model; Immunotherapy; Neuroblastoma; High dose radiation therapy; Combination therapy
• ISSN: 2405-8440; 2405-8440
• DOI: 10.1016/j.heliyon.2023.e17399

The mortality in patients with MYCN-amplified high-risk neuroblastoma remains greater than 50% despite advances in multimodal therapy. Novel therapies are urgently needed that requires preclinical evaluation in appropriate mice models. Combinatorial treatment with high-dose radiotherapy (HDRT) and immunotherapy has emerged as an effective treatment option in a variety of cancers. Current models of neuroblastoma do not recapitulate the anatomic and immune environment in which multimodal therapies can be effectively tested, and there is a need for an appropriate syngeneic neuroblastoma mice model to study interaction of immunotherapy with host immune cells. Here, we develop a novel syngeneic mouse model of MYCN-amplified neuroblastoma and report the relevance and opportunities of this model to study radiotherapy and immunotherapy. A syngeneic allograft tumor model was developed using the murine neuroblastoma cell line 9464D derived a tumor from TH-MYCN transgenic mouse. Tumors were generated by transplanting 1 mm3 portions of 9464D flank tumors into the left kidney of C57Bl/6 mice. We investigated the effect of combining HDRT with anti-PD1 antibody on tumor growth and tumor microenvironment. HDRT (8 Gy x 3) was delivered by the small animal radiation research platform (SARRP). Tumor growth was monitored by ultrasound. To assess the effect on immune cells tumors sections were co-imuunostained for six biomarkers using the Vectra multispectral imaging platform. Tumor growth was uniform and confined to the kidney in 100% of transplanted tumors. HDRT was largely restricted to the tumor region with minimal scattered out-of-field dose. Combinatorial treatment with HDRT and PD-1 blockade significantly inhibited tumor growth and prolonged mice survival. We observed augmented T-lymphocyte infiltration, especially CD3+CD8+ lymphocytes, in tumors of mice which received combination treatment. We have developed a novel syngeneic mouse model of MYCN amplified high-risk neuroblastoma. We have utilized this model to show that combining immunotherapy with HDRT inhibits tumor growth and prolongs mice survival.