Promising systemic immunotherapies in head and neck squamous cell carcinoma.
Promising systemic immunotherapies in head and neck squamous cell carcinoma.
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DOI：
10.1016/j.oraloncology.2013.09.009
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发表时间：
2013-12
期刊：
影响因子：
4.8
通讯作者：
Bauman JE
中科院分区：
文献类型：
--
作者：
Gildener-Leapman N;Ferris RL;Bauman JE
头颈鳞状细胞癌 (HNSCC) 患者在标准治疗中表现出较差的生存率和显着的治疗发病率。 HNSCC 的免疫特征，无论是由致癌物暴露还是人乳头瘤病毒 (HPV) 引起，都具有明显的免疫抑制作用。 HNSCC 免疫疗法的早期临床试验因全身毒性或局部给药困难而受到困扰。现在，由于对 HNSCC 免疫逃避的机制的了解，再加上新型免疫疗法的不断开发，人们对免疫疗法的兴趣重新燃起。本文将总结 HNSCC 的免疫逃逸机制，即肿瘤抗原 (TA) 呈递的下调、信号转导和转录激活因子 (STAT) 家族的异常调节、免疫抑制细胞因子环境以及免疫效应细胞的失调。然后将讨论假设专门对抗 HNSCC 免疫抑制的治疗策略。我们将调查 TA 靶向单克隆抗体 (mAb)，包括原型西妥昔单抗，以及增强抗体依赖性细胞介导的细胞毒性的辅助策略。我们将回顾恢复 STAT1/STAT3 激活平衡的免疫调节。将提供阻断免疫抑制细胞因子（例如白细胞介素 6 或 VEGF）的 mAb 疗法的实例。释放在 HNSCC 中过度表达的 CTLA-4 和 PD-1 等共抑制性 T 细胞受体的 mAb 也具有治疗前景。最后，我们将描述 HPV 相关 HNSCC 的治疗性疫苗接种原则，其中非宿主 TA（如病毒癌蛋白）代表理想的靶标，以及 HPV 阴性 HNSCC，其中 p53 是一个有希望的靶标。对 HNSCC 免疫抑制的深入研究阐明了免疫治疗的机制目标。合理的临床研究可能会导致有效的单独或组合治疗方法。
Patients with head and neck squamous cell carcinoma (HNSCC) demonstrate poor survival and significant treatment morbidity with standard therapy. The immune profile in HNSCC, whether caused by carcinogen exposure or human papillomavirus (HPV), is notably immunosuppressive. Early clinical trials of immunotherapy in HNSCC were troubled by systemic toxicity or difficulties in local administration. Now, interest in immunotherapy has been revitalized by mechanistic insights into immune evasion by HNSCC, coupled to ongoing development of novel immunotherapies. This review will summarize immune escape mechanisms in HNSCC, namely downregulation of tumor antigen (TA) presentation, aberrant regulation of the signal transducer and activator of transcription (STAT) family, the immunosuppressive cytokine milieu, and dysregulation of immune effector cells. Therapeutic strategies hypothesized to specifically counter HNSCC immunosuppression will then be discussed. We will survey TA-targeted monoclonal antibodies (mAb), including the prototype cetuximab, as well as adjunctive strategies to enhance antibody-dependent cell-mediated cytotoxicity. We will review immunomodulation to restore STAT1/STAT3 activation balance. Examples of mAb therapy to block immunosuppressive cytokines, such as interleukin-6 or VEGF, will be provided. mAbs which release co-inhibitory T cell receptors such as CTLA-4 and PD-1, overexpressed in HNSCC, also hold therapeutic promise. Finally, we will describe principles for therapeutic vaccination in HPV-associated HNSCC, where non-host TAs such as viral oncoproteins represent ideal targets, and HPV-negative HNSCC, where p53 is a promising target. Insights into immunosuppression in HNSCC have elucidated mechanistic targets for immunotherapy. Rational clinical investigation may lead to effective stand alone or combinatorial treatment approaches.