Abstract
BackgroundImmune 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 (ΔTL) of peripheral leukocytes as a potential predictive and prognostic marker in patients undergoing ICI therapy.MethodsAge-adapted delta telomere length (ΔTL) of 84 patients treated with ICIs for solid malignancies was measured via quantitative real-time PCR. ΔTL was correlated with outcome and clinical data.ResultsΔTL was not significantly altered between patients with different tumor entities or tumor stages and did not predict tumor response to ICI therapy. However, ΔTLs 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 ΔTL was 5.7 months compared to 18.0 months in patients showing longer ΔTL. The prognostic role of age-adapted ΔTL was further confirmed by uni- and multivariate Cox-regression analyses.ConclusionIn 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.
Highlights
Immune checkpoint inhibitors (ICI) have a wide range of medical applications in various malignancies including lung cancer [1], melanoma [2], renal cell carcinoma [3] and squamous-cell carcinoma of the head and neck [4]
We evaluated whether the individual delta telomere length (DTL) was associated with the occurrence of immune-related adverse events (IRAE) during ICI therapy
In the present study using univariate and multivariate analyses, we show that the individual DTL in our cohort with heterogeneous solid tumors had a significant impact on the patients’ overall survival (OS)
Summary
Immune checkpoint inhibitors (ICI) have a wide range of medical applications in various malignancies including lung cancer [1], melanoma [2], renal cell carcinoma [3] and squamous-cell carcinoma of the head and neck [4]. Further studies indicate that tumors with microsatellite instability (MSI) seem to be characterized by superior response to immunotherapy using ICIs [9]. Other factors such as the tumoral immune cell infiltration, tumor mutational burden, and some tumor specific mutations [e.g. BRAF-mutant non-small cell lung cancer (NSCLC) [10]], have been associated with favorable treatment response [11]. Immune checkpoint inhibitor (ICI) therapy represents a new standard of care for an increasing number of malignancies. We analyze the age-adapted delta telomere length (DTL) of peripheral leukocytes as a potential predictive and prognostic marker in patients undergoing ICI therapy
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