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

• Applicant: Privatdozent Dr. Johannes Döscher
• Subject Area: Otolaryngology, Phoniatrics and Audiology ; Hematology, Oncology
• Term: from 2020 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 451445144

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.

• DFG Programme: WBP Fellowship
• International Connection: United Kingdom
• Host: Professor Christian Ottensmeier, Ph.D.