Serum levels of soluble B and T lymphocyte attenuator predict overall survival in patients undergoing immune checkpoint inhibitor therapy for solid malignancies

TY - JOUR

T1 - Serum levels of soluble B and T lymphocyte attenuator predict overall survival in patients undergoing immune checkpoint inhibitor therapy for solid malignancies

AU - Gorgulho, Joao

AU - Roderburg, Christoph

AU - Heymann, Felix

AU - Schulze-Hagen, Maximilian

AU - Beier, Fabian

AU - Vucur, Mihael

AU - Kather, Jakob N

AU - Laleh, Narmin Ghaffari

AU - Tacke, Frank

AU - Brümmendorf, Tim H

AU - Luedde, Tom

AU - Loosen, Sven H

N1 - © 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

PY - 2021/9/1

Y1 - 2021/9/1

N2 - 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 independent prognostic factor for overall survival (OS). As such, patients with initial sBTLA levels above the calculated prognostic cutoff value (311.64 pg/mL) had a median OS of only 138 days compared to 526 for patients with sBTLA levels below this value (P = .001). Uni- and multivariate Cox regression analyses confirmed the prognostic role of sBTLA in the context of ICI therapy. Finally, we observed a significant correlation between sBTLA levels and the frequency of CD3 + CD8 + BTLA+ T cells in peripheral blood. Thus, our data suggest that circulating sBTLA could represent a noninvasive biomarker to predict outcome to ICI therapy, helping to select eligible therapy candidates.

AB - 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 independent prognostic factor for overall survival (OS). As such, patients with initial sBTLA levels above the calculated prognostic cutoff value (311.64 pg/mL) had a median OS of only 138 days compared to 526 for patients with sBTLA levels below this value (P = .001). Uni- and multivariate Cox regression analyses confirmed the prognostic role of sBTLA in the context of ICI therapy. Finally, we observed a significant correlation between sBTLA levels and the frequency of CD3 + CD8 + BTLA+ T cells in peripheral blood. Thus, our data suggest that circulating sBTLA could represent a noninvasive biomarker to predict outcome to ICI therapy, helping to select eligible therapy candidates.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Biomarkers, Tumor/blood

KW - Case-Control Studies

KW - Female

KW - Follow-Up Studies

KW - Humans

KW - Immune Checkpoint Inhibitors/therapeutic use

KW - Leukocytes, Mononuclear/drug effects

KW - Male

KW - Middle Aged

KW - Neoplasms/blood

KW - Prognosis

KW - Receptors, Immunologic/blood

KW - Survival Rate

U2 - 10.1002/ijc.33610

DO - 10.1002/ijc.33610

M3 - SCORING: Journal article

C2 - 33890289

VL - 149

SP - 1189

EP - 1198

JO - INT J CANCER

JF - INT J CANCER

SN - 0020-7136

IS - 5

ER -