Levels of Bim Protein in T-cells Reflect Success of Anti–PD-1 Cancer Therapy

Measurement of levels of Bim (BCL-2-interacting mediator of cell death) protein in circulating T-cells of cancer patients may provide a less invasive strategy to predict and monitor responses to anti–PD-1 therapy.

Immune checkpoint therapy with PD-1 (Programmed cell death protein 1) blockade has emerged as an effective therapy for many advanced cancers; however, only a small fraction of patients achieve long-term responses. There is no validated blood-based means of predicting the response to PD-1 blockade.

PD-1, functioning as an immune checkpoint, plays an important role in down regulating the immune system by preventing the activation of T-cells, which in turn reduces autoimmunity and promotes self-tolerance. The inhibitory effect of PD-1 is accomplished through a dual mechanism of promoting apoptosis (programmed cell death) in antigen specific T-cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (suppressor T cells).

Investigators at the Mayo Clinic (Rochester, MN, USA) had previously cloned PD-L1 (Programmed death-ligand 1) and found that tumor-associated PD-L1 mediated tumor immune evasion. Since then the group has been working on dissecting the molecular mechanisms of the PD-L1/PD-1 pathway in T-cell dysfunction.

They recently reported that they had identified the protein Bim as a downstream signaling molecule of the PD-1 pathway and that its detection in T-cells was significantly associated with expression of PD-1 and effector T-cell markers. Thus, high levels of Bim in circulating tumor-reactive 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 received anti–PD-1 therapy in the form of the humanized monoclonal antibody drug pembrolizumab. This circulating tumor-reactive T-cell population significantly decreased after successful anti–PD-1 therapy.

"Our previous research demonstrated that Bim is a downstream signaling molecule in the PD-1 signaling pathway, and that levels of Bim reflect the degree of PD-1 interaction with its ligand PD-L1," said senior author Dr. Haidong Dong, associate professor of immunology at the Mayo Clinic. "We hypothesized that the increased frequency of CD8+PD-1+Bim+T cells in patients who respond to immunotherapy reflects an increased number of target T-cells for PD-1 blockade with pembrolizumab, which may explain the positive clinical outcomes in these patients."

The study was published in the May 5, 2016, online edition of the journal JCI Insight.

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