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

越来越多的证据表明，肿瘤放射治疗可以与免疫治疗相结合，使用一定的分割和给药方案，在治疗的原发实体肿瘤内诱导免疫原性抗肿瘤活性。可验证的是，肿瘤照射导致主要组织相容性复合体(MHC)I类表达增强，趋化因子释放，并增强肿瘤相关表位的呈递。此外，放射和抗免疫检查点治疗的组合可以触发足够强大的免疫反应，在某些情况下可能会缩小放射野外的转移性肿瘤。利用放射原发肿瘤作为抗原源的协同效应，激发免疫调节剂增强的全身性抗肿瘤反应，将是一种有趣的新辅助或新转移乳腺癌患者的治疗方法。然而，在乳腺癌的新辅助治疗中，放射治疗通常不被考虑。与食道癌、直肠癌或肛门癌不同，乳腺癌的术前放射治疗研究还很少。在此，我们旨在利用人源化肿瘤小鼠建立类人小鼠模型，系统评价实体瘤照射对固有免疫肿瘤防御和后续免疫检查点(抗PD-L1)靶向的影响。

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.