Immunological Changes under Standard of Care Therapy of Head and Neck Squamous Cell Carcinoma

头颈鳞状细胞癌标准护理治疗下的免疫学变化

• 批准号: 451445144
• 负责人: Privatdozent Dr. Johannes Döscher
• 金额: --
• 依托单位: Universitätsklinik für Hals-, Nasen- und Ohrenheilkunde
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/451445144?language=en
• 关键词: Immunological; Changes; under; Standard; Care

Squamous cell carcinoma of the head and neck still has a poor 5-year survival rate. So-called immune checkpoint modulators have improved survival, but only for a fraction of patients. For advanced carcinomas, primary chemoradiotherapy (CRT) is often the only curative approach. Immunotherapy with a PD-1 antibody has been approved as first-line therapy of choice for recurrent/metastatic disease after primary treatment failure. However, the effect of CRT on the immune system and especially on anti-tumour immunity has hardly been investigated to date. This is especially important, since PD-1 antibodies are being studied in combination with CRT in ongoing clinical trials. The presence of CD8+ T cells in the tumour microenvironment has been shown to be essential for durable anti-tumour control. Recently, a subpopulation of tissue-resident memory cells has been characterized that plays a significant role in the efficacy of immunotherapy. These tissue-resident memory T cells are defined by positivity for CD103, PD1 and TIM3. However, there have been no studies to date on how this immune cell subset is affected by CRT. This will be investigated in more detail in the proposed project. The following hypotheses have been developed:1. Durable response to CRT is dependent on tissue-resident memory T cells. These are reduced in tumours of non-responders after CRT, while immunosuppressive populations remain stable.To verify this hypothesis, a cohort of about 70 patients with biopsies before and after CRT is available. Tissue sections will be analysed by multicolour immunohistochemistry for changes in the tumour microenvironment with respect to the above described T cell populations. The differences between therapy non-responders and patients with complete response are of particular interest.2. Immune signatures differ on RNA level depending on the response to CRT. For this purpose, the above-mentioned biopsies are subjected to RNA analysis using a comprehensive panel of immune-related transcripts. In addition, fresh samples will be collected prospectively and analysed by single-cell RNA-seq in order to gain an ever deeper understanding of observed changes in the tumour microenvironment under CRT. Additionally, adjacent healthy mucosa will be analysed.3. Changes under CRT in the tumour microenvironment differ from changes in peripheral blood.For this purpose, blood was drawn before and after CRT at the time of biopsy. The analysis of the T cell populations is performed by FACS. Peripheral lymphocytes are also analysed at the RNA level to identify intraindividual differences and similarities. This serves mainly to answer the question whether immune monitoring by analysis of peripheral lymphocytes is possible or whether further markers are needed.

头颈部鳞状细胞癌的5年生存率仍然很低。所谓的免疫检查点调节剂提高了生存率，但仅适用于一小部分患者。对于晚期癌症，原发性放化疗（CRT）通常是唯一的治愈方法。使用PD-1抗体的免疫疗法已被批准作为主要治疗失败后复发/转移性疾病的一线治疗选择。然而，CRT对免疫系统，特别是抗肿瘤免疫的影响迄今几乎没有研究。这一点尤其重要，因为PD-1抗体正在进行的临床试验中与CRT联合研究。肿瘤微环境中CD 8 + T细胞的存在已被证明对于持久的抗肿瘤控制至关重要。最近，组织驻留记忆细胞的亚群已被表征为在免疫疗法的功效中起重要作用。这些组织驻留记忆T细胞由CD 103、PD 1和TIM 3的阳性定义。然而，迄今为止还没有关于CRT如何影响这种免疫细胞亚群的研究。这将在拟议项目中进行更详细的调查。提出了以下假设：1.对CRT的持久反应依赖于组织驻留记忆T细胞。这些减少CRT后的无反应者的肿瘤，而免疫抑制人群保持stabil.To验证这一假设，一个队列的约70例患者的活检前后CRT是可用的。将通过多色免疫组织化学分析组织切片中肿瘤微环境相对于上述T细胞群的变化。治疗无应答者和完全应答患者之间的差异特别令人感兴趣。根据对CRT的反应，免疫特征在RNA水平上不同。为此，使用一组全面的免疫相关转录物对上述活检进行RNA分析。此外，将前瞻性地收集新鲜样本，并通过单细胞RNA-seq进行分析，以便更深入地了解CRT下观察到的肿瘤微环境变化。此外，将分析邻近的健康粘膜。CRT下肿瘤微环境的变化与外周血的变化不同，为此，在CRT前后活检时抽血。通过FACS进行T细胞群的分析。还在RNA水平上分析外周淋巴细胞，以确定个体内差异和相似性。这主要用于回答通过分析外周淋巴细胞进行免疫监测是否可能或是否需要进一步标记的问题。