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T cell Bim levels reflect responses to anti-PD-1 cancer therapy
Roxana S Dronca1, Xin Liu2, Susan M Harrington3
1Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA.
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.
Insights
Bim protein levels in T cells can predict patient response to PD-1 blockade cancer immunotherapy. Measuring Bim offers a potential blood test for predicting and monitoring treatment effectiveness.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Immune checkpoint inhibitors targeting PD-1 are effective in advanced cancers but lack predictive biomarkers for durable responses.
- Predicting patient response to PD-1 blockade therapy remains a clinical challenge, with no validated blood-based assays currently available.
Purpose of the Study:
- To investigate Bim as a downstream signaling molecule of the PD-1 pathway.
- To evaluate the prognostic and predictive value of Bim in circulating T cells for anti-PD-1 therapy response in metastatic melanoma.
Main Methods:
- Flow cytometry was used to detect Bim expression in circulating tumor-reactive T cells (PD-1+CD11a(hi)CD8+).
- Correlation analysis was performed between Bim levels, PD-1 expression, effector T cell markers, and patient survival/clinical benefit.
- Changes in circulating tumor-reactive T cells were monitored after anti-PD-1 therapy.
Main Results:
- High Bim levels in circulating tumor-reactive T cells correlated with PD-1 expression and effector T cell markers.
- Elevated Bim predicted poor survival in non-anti-PD-1 treated melanoma patients but predicted clinical benefit in those receiving anti-PD-1 therapy.
- Successful anti-PD-1 therapy led to a significant decrease in the circulating tumor-reactive T cell population.
Conclusions:
- Bim plays a critical role in PD-1/PD-L1-mediated regulation of T cell activation and apoptosis.
- Measuring Bim in circulating T cells may offer a non-invasive method to predict and monitor anti-PD-1 therapy response.
- Further prospective studies are required to validate Bim as a predictive biomarker for PD-1 blockade immunotherapy.
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