Telomere Shortening In Peripheral Leukocytes Is Associated With Poor Survival In Cancer Patients Treated With Immune Checkpoint Inhibitor Therapy

Background Immune checkpoint inhibitor (ICI) therapy represents a new standard of care for an increasing number of malignancies. Nevertheless, response rates and outcome of ICI treatment vary between individuals and the identification of predictive markers or hints towards immune cell exhaustion during therapy has remained a major challenge. Leukocyte telomere length is an established predictive biomarker of replicative aging and cellular proliferative potential in various hematological diseases. However, its relevance in the context of ICI therapy has not been investigated to date. Here, we analyze the age-adapted delta telomere length (Delta TL) of peripheral leukocytes as a potential predictive and prognostic marker in patients undergoing ICI therapy. Methods Age-adapted delta telomere length (Delta TL) of 84 patients treated with ICIs for solid malignancies was measured via quantitative real-time PCR. Delta TL was correlated with outcome and clinical data. Results Delta TL was not significantly altered between patients with different tumor entities or tumor stages and did not predict tumor response to ICI therapy. However, Delta TLs at initiation of treatment were a prognostic marker for overall survival (OS). When using a calculated ideal cut-off value, the median OS in patients with shorter Delta TL was 5.7 months compared to 18.0 months in patients showing longer Delta TL. The prognostic role of age-adapted Delta TL was further confirmed by uni- and multivariate Cox-regression analyses. Conclusion In the present study, we demonstrate that shorter telomere lengths in peripheral blood leukocytes are associated with a significantly impaired outcome in patients receiving ICI therapy across different malignancies. We explain our findings by hypothesizing an older replicative age in peripheral leukocytes of patients with an impaired overall survival, reflected by a premature TL shortening. Whether this association is ICI-specific remains unknown. Further follow-up studies are needed to provide insights about the exact mechanism of how shortened telomeres eventually affect OS and could help guiding therapeutic decisions in future.