Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK
Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK.
J Immunother Cancer. 2022 Mar;10(3). doi: 10.1136/jitc-2021-004306.
Despite therapeutic gains from immune checkpoint inhibitors (ICI) in many tumor types, new strategies are needed to extend treatment benefits, especially in patients failing to mount effective antitumor T-cell responses. Radiation and drug therapies can profoundly affect the tumor immune microenvironment. Here, we aimed to identify immunotherapies to increase the antitumor response conferred by combined ataxia telangiectasia and Rad3-related kinase inhibition and radiotherapy.
Using the human papillomavirus (HPV)-negative murine oral squamous cell carcinoma model, MOC2, we assessed the nature of the antitumor response following ataxia telangiectasia and Rad3-related inhibitor (ATRi)/radiotherapy (RT) by performing RNA sequencing and detailed flow cytometry analyses in tumors. The benefit of immunotherapies based on T cell immunoreceptor with Ig and ITIM domains (TIGIT) and Programmed cell death protein 1 (PD-1) immune checkpoint blockade following ATRi/RT treatment was assessed in the MOC2 model and confirmed in another HPV-negative murine oral squamous cell carcinoma model called SCC7. Finally, immune profiling was performed by flow cytometry on blood samples in patients with head and neck squamous cell carcinoma enrolled in the PATRIOT clinical trial of combined ATRi/RT.
ATRi enhances radiotherapy-induced inflammation in the tumor microenvironment, with natural killer (NK) cells playing a central role in maximizing treatment efficacy. We demonstrated that antitumor activity of NK cells can be further boosted with ICI targeting TIGIT and PD-1. Analyses of clinical samples from patients receiving ATRi (ceralasertib) confirm the translational potential of our preclinical studies.
This work delineates a previously unrecognized role for NK cells in the antitumor immune response to radiotherapy that can be augmented by small-molecule DNA damage-response inhibitors and immune checkpoint blockade.
尽管免疫检查点抑制剂（ICI）在许多肿瘤类型中带来了治疗上的收益，但仍需要新的策略来扩大治疗效益，尤其是在那些无法产生有效抗肿瘤 T 细胞反应的患者中。放疗和药物治疗可以深刻地影响肿瘤免疫微环境。在这里，我们旨在确定免疫疗法，以增加联合共济失调毛细血管扩张症和 Rad3 相关激酶抑制和放疗所赋予的抗肿瘤反应。
我们使用人乳头瘤病毒（HPV）阴性的小鼠口腔鳞状细胞癌模型 MOC2，通过对肿瘤进行 RNA 测序和详细的流式细胞术分析，评估了共济失调毛细血管扩张症和 Rad3 相关抑制剂（ATRi）/放疗（RT）后抗肿瘤反应的性质。在 MOC2 模型中评估了基于 T 细胞免疫受体与 Ig 和 ITIM 结构域（TIGIT）和程序性细胞死亡蛋白 1（PD-1）免疫检查点阻断的免疫疗法在 ATRi/RT 治疗后的获益，并在另一个称为 SCC7 的 HPV 阴性小鼠口腔鳞状细胞癌模型中得到了证实。最后，通过流式细胞术对参加 PATRIOT 临床试验的接受 ATRi/RT 联合治疗的头颈部鳞状细胞癌患者的血液样本进行免疫分析。
ATRi 增强了肿瘤微环境中的放疗诱导的炎症，其中自然杀伤（NK）细胞在最大限度地提高治疗效果方面发挥着核心作用。我们证明，针对 TIGIT 和 PD-1 的 ICI 可以进一步增强 NK 细胞的抗肿瘤活性。对接受 ATRi（ceralasertib）治疗的患者的临床样本进行分析证实了我们的临床前研究具有转化潜力。
这项工作描绘了 NK 细胞在放疗抗肿瘤免疫反应中的一个以前未被认识的作用，这种作用可以通过小分子 DNA 损伤反应抑制剂和免疫检查点阻断来增强。
Zotero 插件
