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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 3

Bim upregulation negatively affects the survival of melanoma patients.

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Bim upregulation negatively affects the survival of melanoma patients.
(...
(A) The optimal cut-off point of Bim levels was defined as the mean Bim levels (mean fluorescence intensity [MFI]) of healthy donors (n = 10) plus 2 SD, i.e., 15.4 + 10.5 × 2 = 36.4 (Bim MFI). This cut-off point of Bim MFI is closer to the mean Bim MFI (39.1) of melanoma patients (n = 19). (B) The survival curve of melanoma patients with high (n = 11) or low (n = 8) Bim levels in their tumor-reactive CD8+ T cells (P = 0.006). Data in B were analyzed using log-rank (Mantel-Cox) test.

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