Die immunologische Tumormikroumgebung in plattenepithelialen Tumoren des Kopf-Hals-Bereichs – ein bedeutender Einflussfaktor auf Therapie und Prognose

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous tumor entity that includes tumors of the lip and oral cavity as well as the pharynx (nasopharynx, oropharynx, hypopharynx) and larynx. Overall, HNSCC is currently the eighth most common tumor entity worldwide with more than
800,000 cases per year (54). The main risk factors for tumor development are tobacco and alcohol consumption and, particularly in oropharyngeal carcinoma, chronic infection with a high-risk type of the human papillomavirus (HPV) (22, 30, 42). The majority of patients with the disease are male and the average age of onset is around 65 years (29, 54).
The prognosis at diagnosis is still poor. Although the 5-year survival rate in the localized tumour stage is 68-84%, it is only 33-65% in the regionally advanced tumour stage and 8-35% in the presence of distant metastases (18, 52, 56). Due to the usually late diagnosis, in which over 60% of HNSCC patients are already in advanced tumor stage III or IV, and the frequent occurrence of tumor recurrence in up to 60% of cases, the overall 5-year survival rate is between 40-65% (1, 49, 52).

The aim of the studies presented below was to better characterize the TIME of patients with head and neck cancer and to determine important influencing factors in order to develop possible new immunotherapeutic targets and improve existing therapy concepts.
First, we compiled a comprehensive retrospective cohort of patients from whom tumor material was available for further analysis and clinical-pathological data. This cohort was used to develop the research questions of the first three original papers listed. For original work 3, it was also possible to draw on an extensive HNSCC validation cohort from the Institute of Pathology at Bonn University Hospital. In original work 1, we worked out whether it is possible to make a statement about the distribution and composition of the immune cell infiltrate in the routine hematoxylin-eosin (HE) stained histologic section to make a statement about the prognosis.
Original work 2 was dedicated to the question of whether the use of different anti-PDL1 antibodies in the immunohistochemical determination of PDL1 expression yields equivalent results. In most cases, the further therapeutic decision to use immune checkpoint inhibitors is based on the evaluation of PDL1 expression.
Original work 3 dealt with differences in the composition of the tumor immune infiltrate of primary tumors and recurrences and their influence on the development of recurrence as well as the connection with previous chemoradiotherapy (CRT). The aim of the differentiation of the immune infiltrate of tumor recurrence from the primary tumor, which was carried out for the first time in this study, was to create an immuno-oncological basis for improving the still severely limited treatment options in the recurrence situation. In original work 4, we performed a bioinformatic in silico analysis of HNSCC using freely available expression and mutation data from The Cancer Genome Atlas (TCGA) database to identify potential new therapeutic targets that have an impact on an effective antitumor immune response.
We identified the histone acetyltransferase E1A binding protein P300 (EP300) as an important modulator of TIME in HNSCC as well as in a variety of other solid tumor entities and elucidated the underlying mechanisms using the underlying mechanisms by means of functional analyses.