抗体靶向厌氧菌点燃“冷”肿瘤并改善放疗的旁观效应

Antibody targeting of anaerobic bacteria warms cold tumors and improves the abscopal effect of radiotherapy

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Journal of Translational Medicine

影响因子:7.5

分区:医学2区 Top / 医学：研究与实验2区

发表日期:2024 Jul 15

作者: WeiZhou Wang, YunXue Zheng, ZhouXue Wu, Min Wu, Yue Chen, Yan Zhang, ShaoZhi Fu, JingBo Wu

DOI: 10.1186/s12967-024-05469-0

摘要

免疫检查点抑制剂与放疗结合可以增强放疗的免疫调节作用，并减少远端未照射肿瘤的生长（旁观效应）；然而，当前效果仍不理想。因此，需要新的治疗策略以增强这一效应。我们之前的研究显示，双歧杆菌（Bi）及其特异性单克隆抗体（mAb）可以靶向并缓解肿瘤部位的缺氧状态，充当放射增敏剂。本研究探索了四联疗法（Bi + mAb与放疗 + αPD-1）的抗肿瘤效果。通过肿瘤体积测量、存活分析、PET/CT成像、免疫细胞浸润分析和细胞因子表达水平，为该组合疗法的整体影响提供了全面图景。结果显示，旁观效应在“冷”肿瘤模型中得到进一步放大，延长了肿瘤负荷小鼠的生存时间。Bi可以在原发和继发肿瘤中定植，并引导抗体到达肿瘤部位，激活补体、增强抗体依赖性细胞毒（ADCC）效应，启动先天免疫反应。随后，结合αPD-1和放疗刺激适应性免疫反应，与细胞因子协同作用，扩大免疫效果，产生有效的抗肿瘤免疫反应。Bi作为人工植入的厌氧靶点，在肿瘤中引发短暂的“感染”，使肿瘤局部发炎变“热”；同时，抗体靶向Bi以增强肿瘤局部免疫效果，再结合放疗和αPD-1，从多维度放大旁观效应。因此，本研究为抗体靶向厌氧菌多功能免疫激活在放疗治疗广泛转移性癌症中的新应用提供了新思路。

Abstract

The combination of immune checkpoint inhibitors with radiotherapy can enhance the immunomodulation by RT and reduce the growth of distant unirradiated tumors (abscopal effect); however, the results are still not very satisfactory. Therefore, new treatment options are needed to enhance this effect. Our previous study showed that the combination of Bifidobacterium (Bi) and its specific monoclonal antibody (mAb) could target and alleviate hypoxia at the tumor site and act as a radiosensitizer. In this study, we explored the anti-tumor efficacy of quadruple therapy (Bi + mAb and RT + αPD-1). The current study also aimed to probe into the complex immune mechanisms underlying this phenomenon.Constructed 4T1 breast and CT26 colon cancer tumor models. A comprehensive picture of the impact of constructed quadruple therapy was provided by tumor volume measurements, survival analysis, PET/CT imaging, immune cell infiltration analysis and cytokine expression levels.The abscopal effect was further amplified in the "cold" tumor model and prolonged survival in tumor-bearing mice. Bi can colonized in primary and secondary tumors and direct the mAb to reach the tumor site, activate complement, enhance the ADCC effect and initiate the innate immune response. Then combined with αPD-1 and radiotherapy to stimulate adaptive immune response and synergize with cytokines to expand the immune efficacy and generate effective anti-tumor immune response.Bi was used as an artificially implanted anaerobic target to cause a transient "infection" at the tumor, causing the tumor to become locally inflamed and "hot", and at the same time, mAb was used to target Bi to enhance the local immune effect of the tumor, and then combined with radiotherapy and αPD-1 to amplify the abscopal effect in multiple dimensions. Therefore, the present study provided a new idea for the multipotent immune-activating function of antibody-targeted anaerobic bacteria for the RT treatment of extensively metastasized cancer patients.