Background: Immune checkpoint inhibitors (ICIs) represent a new therapeutic standard for an increasing number of tumor entities. Nevertheless, individual response and outcome to ICI is very heterogeneous, and the identification of the ideal ICI candidate has remained one of the major issues. Sarcopenia and the progressive loss of muscle mass and strength, as well as muscular fat deposition, have been established as negative prognostic factors for a variety of diseases, but their role in the context of ICI therapy is not fully understood. Here, we have evaluated skeletal muscle composition as a novel prognostic marker in patients undergoing ICI therapy for solid malignancies. Methods: We analyzed patients with metastasized cancers receiving ICI therapy according to the recommendation of the specific tumor board. Routine CT scans before treatment initialization and during ICI therapy were used to assess the skeletal muscle index (L3SMI) as well as the mean skeletal muscle attenuation (MMA) in n = 88 patients receiving ICI therapy. Results: While baseline L3SMI and MMA values were unsuitable for predicting the individual response and outcome to ICI therapy, longitudinal changes of the L3SMI and MMA (∆L3SMI, ∆MMA) during ICI therapy turned out to be a relevant marker of therapy response and overall survival. Patients who responded to ICI therapy at three months had a significantly higher ∆L3SMI compared to non-responders (−3.20 mm2/cm vs. 1.73 mm2/cm, p = 0.002). Moreover, overall survival (OS) was significantly lower in patients who had a strongly decreasing ∆L3SMI (<−6.18 mm2/cm) or a strongly decreasing ∆MMA (<−0.4 mm2/cm) during the first three month of ICI therapy. Median OS was only 127 days in patients with a ∆L3SMI of below −6.18 mm2/cm, compared to 547 days in patients with only mildly decreasing or even increasing ∆L3SMI values (p < 0.001). Conclusion: Both progressive sarcopenia and an increasing skeletal muscle fat deposition are associated with poor response and outcome to ICI therapy, which might help to guide treatment decisions during ICI therapy.

Therapy with immune checkpoint inhibitors (ICIs) can lead to durable tumor control in patients with various advanced stage malignancies. However, this is not the case for all patients, leading to an ongoing search for biomarkers predicting response and outcome to ICI. The B and T lymphocyte attenuator (BTLA) is an immune checkpoint expressed on immune cells that was shown to modulate therapeutic responses. Here, we evaluate circulating levels of its soluble form, soluble B and T lymphocyte attenuator (sBTLA), as a biomarker for the prediction of treatment response and outcome to ICI therapy. Serum levels of sBTLA were analyzed by multiplex immunoassay in n = 84 patients receiving ICI therapy for solid malignancies and 32 healthy controls. BTLA expression was evaluated on peripheral blood mononuclear cells in a subset of patients (n = 6) using multicolor flow cytometry. Baseline sBTLA serum levels were significantly higher in cancer patients compared to healthy controls. Importantly, circulating sBTLA levels were an

suPAR pre-OP Log-rank = 8.003 p = 0.005 2,500 Overall survival Circulating suPAR Biliary Tract Cancer (BTC) Highlights Biliary tract cancer is associated with poor outcomes and increasing incidence. Surgical resection is the only potentially curative treatment option for patients with biliary tract cancer. The identification of ideal surgical candidates has remained challenging. Circulating suPAR represents a novel diagnostic and prognostic biomarker in resectable patients. SuPAR might be useful to identify patients with biliary tract cancer who will benefit most from tumor resection.

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.