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Monitoring PD-1-Blocking Antibodies Bound to T Cells Derived from a Drop of Peripheral Blood
Published on: February 5, 2020
Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints
Shohei Koyama1,2, Esra A Akbay2,3, Yvonne Y Li2,3
1Department of Medical Oncology and Cancer Vaccine Center, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Abstract:
Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.
Insights
Resistance to PD-1 blockade in lung cancer can be overcome by targeting the TIM-3 immune checkpoint. Upregulation of TIM-3 in T cells suggests it is a biomarker for adaptive resistance to PD-1 therapy.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Antibodies targeting the PD-1/PD-L1 immune checkpoint show significant antitumour activity in lung cancer.
- Increasing resistance to these therapies necessitates understanding adaptive resistance mechanisms.
Purpose of the Study:
- To investigate the tumour immune microenvironment in lung adenocarcinoma models resistant to anti-PD-1 therapy.
- To identify alternative immune checkpoints involved in adaptive resistance.
Main Methods:
- Analysis of the tumour immune microenvironment in immunocompetent mouse models of lung adenocarcinoma undergoing anti-PD-1 therapy.
- Assessment of T-cell immunoglobulin mucin-3 (TIM-3) expression in T cells from progressing tumors.
- Evaluation of combination therapy with PD-1 and TIM-3 blocking antibodies.
- Analysis of TIM-3 expression in patients with adaptive resistance to anti-PD-1 treatment.
Main Results:
- Upregulation of alternative immune checkpoints, particularly TIM-3, was observed in T cells within tumors progressing after anti-PD-1 therapy.
- Addition of a TIM-3 blocking antibody improved survival in models that failed PD-1 blockade.
- Two patients developing adaptive resistance showed similar TIM-3 upregulation in T cells at treatment failure.
Conclusions:
- Upregulation of TIM-3 is associated with adaptive resistance to PD-1 blockade in lung cancer.
- TIM-3 represents a potential therapeutic target and a biomarker for predicting resistance to PD-1 therapy.
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