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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 1

Bim upregulation in tumor-reactive CD8+ T cells is dependent on PD-1 and PD-L1 interaction.

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Bim upregulation in tumor-reactive CD8+ T cells is dependent on PD-1 and...
(A) Higher Bim expression (mean fluorescence intensity [MFI], mean ± SD) by PD-1+CD11ahiCD8+ T cells isolated from B16 melanoma tumors. (B) Higher frequency of Bim+ cells among PD-1+CD8+ T cells isolated from B16 tumors of WT and Bim KO mice. (C) Lower Bim expression by CD8+ T cells isolated from B16 tumors in PD-1 KO mice than WT mice. Data in A–C were analyzed using Mann-Whitney U test, *P < 0.05, **P < 0.01. (D) Bim expression by CD8+ T cells isolated from WT and PD-L1 KO breast tumors. Data are from 3 to 5 mice per group and are representative of 2 independent experiments. Data were analyzed using a paired 2-tailed Student t test, *P < 0.05. (E) PD-1 antibody (G4) or control IgG reduced Bim levels (MFI) in PD-1+CD11ahiCD8+ T cells in PD-L1 WT, but not in PD-L1 KO, tumor tissues. Data were analyzed via 1-way ANOVA with a Newman-Keuls multiple comparison test, *P < 0.05.
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