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

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.

Immune Activation, Exhaustion and Senescence Profiles as Possible Predictors of Cancer in Liver Transplanted Patients

“…In a previous study, we found that low telomere length is associated with a higher risk of tumor onset ( 17 ). In the transplantation field, shorter telomere length in peripheral blood leukocytes was associated with a significantly worse clinical response in patients receiving immune checkpoint inhibitor therapy across different malignancies and the calculated relative telomere length differences defined as “delta telomere length” was found to be an independent predictor of overall survival ( 39 ). In our study, liver transplanted patients who developed a tumor presented a longer telomere length at baseline, but tended to undergo to a higher telomere erosion between the baseline and the tumor onset compared to LT-no-PTM patients during the same follow-up period.…”

Cellular aging is accelerated in the malignant clone of myeloproliferative neoplasms

“…Cryopreserved whole blood cells after red blood cell depletion were used for the flow- fluorescent in-situ hybridization (flow-FISH) analysis of TL in lymphocytes and granulocytes (18). Alternatively, TL of colonies derived from CFUs, CD34 + and PBMC cell fractions were analyzed by telomere-PCR (TEL-PCR) (20).…”

Cancer treatment-induced NAD+ depletion in premature senescence and late cardiovascular complications

“…The St. Jude Lifetime Cohort Study (SJLIFE) revealed a significantly shorter telomere length in leukocytes of childhood cancer survivors relative to that of the age- and sex-matched controls [ 54 ] . Patients with solid malignancies received immune checkpoint inhibitors revealed a link between peripheral leukocyte telomere shortening and poor survival [ 55 ] . Mammalian telomeres are protected by Shelterin, a protein complex composed of six proteins including TERF telomeric repeat binding factor 1 (TRF1) [ 56 ] , TERF telomeric repeat binding factor 2 (TRF2) [ 57 ] , telomeric repeat-binding factor 2-interacting protein 1 [TERF2IP, or repressor/activator protein 1 (RAP1)] [ 58 ] , the protection of telomeres 1 (POT1) [ 59 ] , TPP1 [ 60 ] , and TRF1-interacting nuclear factor 2 (TIN2) [ 61 , 62 ] .…”