Assessment of the impact of low dose solid tumor irradiation on tumor growth, metastases, immune cell activation, and subsequent immunotherapy in a humanized tumor mouse model

评估低剂量实体瘤照射对人源化肿瘤小鼠模型中肿瘤生长、转移、免疫细胞激活和后续免疫治疗的影响

• 批准号: 416917226
• 负责人: Professor Dr. Gero Brockhoff, Ph.D.
• 金额: --
• 依托单位: Arbeitsgruppe Zytometrische und zelluläre Onkologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/416917226?language=en
• 关键词: Assessment; impact; low; dose; solid

There is mounting evidence that tumor irradiation can be applied in a combination with immunotherapy using certain fractionation and dosing schedules to elicit immunogenic anti-tumor activity within the treated primary solid tumor. Verifiably, tumor irradiation causes an enhanced upregulation of major histocompatibility complex (MHC) class I expression, the release of chemokines, and enhanced presentation of tumor associated epitopes. Moreover, the combination of radiation and an anti-immune checkpoint treatment can trigger a potent enough immune response that in some cases may shrink metastatic tumors outside of the radiation field. Exploiting synergistic effects by using the radiated primary tumor as an antigen source to provoke a potent systemic antitumor response augmented by immunomodulators would be an intriguing treatment approach for neoadjuvant or de-novo metastatic breast cancer patients. However, radiotherapy is not usually considered in the context of neoadjuvant therapy for breast cancer. Unlike esophageal, rectal or anal cancer, preoperative radiotherapy has been little studied in breast cancer yet. Here we aim to systematically evaluate the effect of bulk tumor irradiation on the inherent immunological tumor defense and on subsequent immune-checkpoint (anti-PD-L1) targeting in a human-like mouse model using so called humanized tumor mice.

越来越多的证据表明，肿瘤放射可以与免疫疗法结合使用，使用某些分次和给药方案来在治疗的原发性实体瘤中引发免疫原性抗肿瘤活性。经验证，肿瘤照射会导致主要组织相容性复合体 (MHC) I 类表达的增强上调、趋化因子的释放以及肿瘤相关表位的增强呈现。此外，放射和抗免疫检查点治疗的结合可以引发足够有效的免疫反应，在某些情况下可能会缩小放射野之外的转移性肿瘤。通过使用放射的原发肿瘤作为抗原源来激发由免疫调节剂增强的有效的全身抗肿瘤反应，从而利用协同效应，对于新辅助或从头转移性乳腺癌患者来说将是一种有趣的治疗方法。然而，在乳腺癌新辅助治疗中通常不考虑放疗。与食管癌、直肠癌或肛门癌不同，乳腺癌术前放疗的研究还很少。在这里，我们的目标是在使用所谓的人源化肿瘤小鼠的类人小鼠模型中系统地评估体肿瘤照射对固有免疫肿瘤防御和随后的免疫检查点（抗PD-L1）靶向的影响。