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Selected Publication:
Kaiser, M.
Genomic biomarkers and immune checkpoint Inhibitor response in lung cancer and TZAP induced telomere trimming in ALT cells
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] 2; 2024. pp. 119
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- Authors Med Uni Graz:
- Advisor:
- Gerger Armin
- Herrmann Markus
- Renner Wilfried
- Altmetrics:
- Abstract:
- First part: Telomere dynamics and immune checkpoint inhibitor response in lung cancer (TILUC). The treatment of patients with non-small-cell lung cancer (NSCLC) has seen remarkable benefits with the use of immune checkpoint inhibitors (ICIs). To establish an effective treatment strategy with improved outcome it is essential to determine biomarkers that identify responders and to avoid immunotoxicities. Telomeres impact the proliferative potential of T-cells, which make up the tumor-specific activated population in immunotherapy. In this study, the role of telomere length (TL), TERT expression and single nucleotide polymorphisms related to TL were investigated, to determine their potential as a predictive marker regarding survival in patients receiving immune checkpoint therapy. Samples were obtained before initiation of therapy and at follow-up examinations after approximately three months for up to one year. In the Kaplan-Meier analysis, short telomeres at three months after treatment initiation but not at baseline, was negatively associated with overall survival. In multivariate analysis, when age, sex, PDL-1 expression, and histology were included, the result was not statistically significant. It appeared that telomere length at three months but not age, sex or PD-L1 expression was predictive of survival. Furthermore, TERT expression and SNP analysis seem not to be of predictive value. Hence, the determination of telomere length in T-cells after treatment initiation could be useful for individualized treatment decisions. Second part: TZAP-induced telomere trimming in ALT cells. The telomere binding protein TZAP has recently emerged as a crucial regulator of telomere length homeostasis, specifically in cancer and stem cells, by controlling the upper limit of telomere length through a process known as telomere trimming. Despite its significance, the precise mechanism by which TZAP accomplishes this task has remained elusive. Recent findings have shed light on the recruitment of TZAP to telomeres, revealing that it requires an open telomeric chromatin structure. Additionally, it appears that the chromatin remodeler ATRX/DAXX plays a central role in preventing the decompaction of telomeric chromatin and the subsequent telomere trimming induced by TZAP. Furthermore, the data suggests that TZAP binding to telomeres triggers telomere trimming by inducing replication stress and activating an alternative lengthening of telomeres (ALT)-like pathway that depends on the involvement of the Bloom-Topoisomerase IIIα-RMI1-RMI2 (BTR) complex.