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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 4

Bim upregulation in effector CD8+ T cells.

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Bim upregulation in effector CD8+ T cells.
(A) Positive correlations bet...
(A) Positive correlations between Bim and granzyme B (n = 19) or T-bet (n = 26) levels in CD11ahiCD8+ T cells of melanoma patients. (B) High Bim and PD-1 expression in IFN-γ–producing CD8+ T cells stimulated with PMA and ionomycin. (C) Tumor antigen-specific effector (IFN-γ+) CD8+ T cells have higher expression of Bim and PD-1 than noneffector (IFN-γ–) cells. Data in A and B were analyzed by Pearson correlation test. Data in C are from 4 MM patients per group and are representative of 2 independent experiments, *P < 0.05 (2-tailed unpaired t test). (D) Frequency of PD-1+CD11ahi cells among CD8+ T cells within B16 tumor tissues of WT and Bim KO mice (n = 9). The right-sided graphs show percentages of CD8+ T cells in tumor-infiltrating lymphocytes. (E) Frequency of IFN-γ–producing CD8+ T cells from tumor tissues of WT and Bim KO mice (n = 8). The background production of IFN-γ was shown in spleens of naive mice. Data in D and E were analyzed by Mann-Whitney U test, *P < 0.05, **P < 0.01.

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