1 Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
2 Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, USA.
J Dent Res. 2019 Sep;98(10):1073-1080. doi: 10.1177/0022034519864112. Epub 2019 Jul 24.
The success of immune checkpoint receptor blockade has brought exciting promises for the treatment of head and neck squamous cell carcinoma (HNSCC). While patients who respond to checkpoint inhibitors tend to develop a durable response, <15% of patients with HNSCC respond to immune checkpoint inhibitors, underscoring the critical need to alleviate cancer resistance to immunotherapy. Major advances have been made to elucidate the intrinsic and adaptive resistance mechanisms to immunotherapy. Central genomic events in HNSCC have been found to possess previously unknown roles in suppressing immune sensing. Such inhibitory function affects both the innate and adaptive arms of tumor-specific immunity. While checkpoint blockade effectively reinvigorates adaptive T-cell responses, additional targeting of the oncogenic inhibitors of innate immune sensing likely informs a novel and potent strategy for immune priming. This review discusses the recent advances on the identification of key HNSCC oncogenes that impair antitumor immunity and emerging immune-priming approaches that sensitize poorly immunogenic HNSCCs to checkpoint blockade. These approaches include but are not limited to cancer vaccine systems utilizing novel type I interferon agonists as immune adjuvants, radiation, DNA damage-inducing agents, and metabolic reprogramming. The goal of these multipronged approaches is to expand tumor-specific effector T-cells, break checkpoint receptor-mediated tolerance, and metabolically support sustained T-cell activation. The translation of therapeutics that reverses oncogenic inhibition of immune sensing requires thorough characterization of the HNSCC regulators of innate immune sensors, development of additional immunocompetent HNSCC mouse models, as well as engineering of more robust immune adjuvant delivery systems. Built on the success of checkpoint blockade, validation of novel immune-priming approaches holds key promises to expand the pool of responders to immunotherapy.
免疫检查点受体阻断的成功为头颈部鳞状细胞癌（HNSCC）的治疗带来了令人兴奋的前景。虽然对检查点抑制剂有反应的患者往往会产生持久的反应，但<15%的 HNSCC 患者对免疫检查点抑制剂有反应，这突显了缓解癌症对免疫疗法的耐药性的迫切需要。在阐明免疫治疗的内在和适应性耐药机制方面取得了重大进展。已经发现 HNSCC 中的主要基因组事件在抑制免疫感应方面具有以前未知的作用。这种抑制功能影响肿瘤特异性免疫的先天和适应性臂。虽然检查点阻断有效地重新激活适应性 T 细胞反应，但对先天免疫感应的致癌抑制剂进行额外靶向可能为免疫启动提供一种新颖而有效的策略。这篇综述讨论了最近在鉴定破坏抗肿瘤免疫的关键 HNSCC 癌基因方面的进展，以及新兴的免疫启动方法，这些方法使免疫原性差的 HNSCC 对检查点阻断敏感。这些方法包括但不限于利用新型 I 型干扰素激动剂作为免疫佐剂的癌症疫苗系统、辐射、诱导 DNA 损伤的药物和代谢重编程。这些多管齐下方法的目标是扩大肿瘤特异性效应 T 细胞，打破检查点受体介导的耐受性，并代谢支持持续的 T 细胞激活。逆转免疫感应的致癌抑制的治疗方法的转化需要对先天免疫传感器的 HNSCC 调节剂进行彻底表征，开发额外的免疫功能健全的 HNSCC 小鼠模型，以及工程更强大的免疫佐剂递送系统。在检查点阻断成功的基础上，验证新的免疫启动方法有望扩大对免疫疗法有反应的人群。
