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T cell Bim levels reflect responses to anti–PD-1 cancer therapy
Roxana S. Dronca, … , Svetomir N. Markovic, Haidong Dong
Roxana S. Dronca, … , Svetomir N. Markovic, Haidong Dong
Published May 5, 2016
Citation Information: JCI Insight. 2016;1(6):e86014. https://doi.org/10.1172/jci.insight.86014.
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Research Article Oncology

T cell Bim levels reflect responses to anti–PD-1 cancer therapy

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Abstract

Immune checkpoint therapy with PD-1 blockade has emerged as an effective therapy for many advanced cancers; however, only a small fraction of patients achieve durable responses. To date, there is no validated blood-based means of predicting the response to PD-1 blockade. We report that Bim is a downstream signaling molecule of the PD-1 pathway, and its detection in T cells is significantly associated with expression of PD-1 and effector T cell markers. High levels of Bim in circulating tumor-reactive (PD-1+CD11ahiCD8+) T cells were prognostic of poor survival in patients with metastatic melanoma who did not receive anti–PD-1 therapy and were also predictive of clinical benefit in patients with metastatic melanoma who were treated with anti–PD-1 therapy. Moreover, this circulating tumor-reactive T cell population significantly decreased after successful anti–PD-1 therapy. Our study supports a crucial role of Bim in both T cell activation and apoptosis as regulated by PD-1 and PD-L1 interactions in effector CD8+ T cells. Measurement of Bim levels in circulating T cells of patients with cancer may provide a less invasive strategy to predict and monitor responses to anti–PD-1 therapy, although future prospective analyses are needed to validate its utility.

Authors

Roxana S. Dronca, Xin Liu, Susan M. Harrington, Lingling Chen, Siyu Cao, Lisa A. Kottschade, Robert R. McWilliams, Matthew S. Block, Wendy K. Nevala, Michael A. Thompson, Aaron S. Mansfield, Sean S. Park, Svetomir N. Markovic, Haidong Dong

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Figure 6

Changes of Bim levels predict responses to anti–PD-1 therapy in melanoma patients.

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Changes of Bim levels predict responses to anti–PD-1 therapy in melanoma...
(A) Bim levels (frequency [%] and mean fluorescence intensity [MFI]) among PD-1+CD11ahiCD8+ T cells at baseline in melanoma patients with progressive diseases (n = 7) and responders (n = 6). (B) Percentages of changes in the frequency of Bim+ cells among PD-1+CD11ahiCD8+ T cells at 12 weeks after anti–PD-1 (pembrolizumab) therapy of the same cohort of patients as in B. Data in A and B were analyzed by nonparametric Mann-Whitney test, *P < 0.05, **P < 0.01; error bars, median with interquartile ranges. (C) Imaging of metastatic melanoma (red arrows) in one patient with pseudoprogression at 12 weeks after anti–PD-1 therapy. (D) The changes of Bim levels (% and MFI) among circulating PD-1+CD11ahiCD8+ T cells of this patient at baseline and 12 and 16 weeks after PD-1 therapy.

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