Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints

By S. Koyama, Esra A. Akbay, Yvonne Y. Li, G. Herter-Sprie, Kevin A. Buczkowski, W. Richards, L. Gandhi, Amanda J. Redig, S. Rodig, H. Asahina and 16 more. Nature Communications, 2016

1,425 citations recorded by the source corpus.

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. Blocking immune checkpoints is a promising strategy to treat lung cancer, but patients often become resistant to the therapy. Here, the authors analyse resistance in mouse models of lung cancer and show in mice and two patients, an increase in the expression of TIM3, which is also involved in the immune response to cancer.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/0ad306fa4436b25261fc374caa947488a0dcbed6

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Citations in the corpus

The head and neck cancer immune landscape and its immunotherapeutic implications. (2016, background): “checkpoint adaptive resistance recently observed in lung adenocarcinoma (74).”
Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018, background): “Another study noted the upregulation of the inhibitory receptor TIM-3 (but not VISTA) on the surface of T cells in anti-PD-1-treated mice with lung cancer as well as TIM-3 upregulation on T cells in adenocarcinoma patients refractory to PD-1 treatment (113).”
Acquired Resistance to Immune Checkpoint Inhibitors (2020, background): “(E) Additional inhibitory checkpoints: upregulation of additional immune checkpoints such as TIM3, LAG3, and VISTA can be found at the time of acquired resistance, and may reflect terminal exhaustion and fixed loss of effector function.”
Mechanisms of resistance to immune checkpoint inhibitors (2018, background): “…in the setting of an oncogenic KRas mutation promotes elaboration of IL-6, which recruits neutrophils, decreases T-cell infiltration, and was associated with higher levels of T-cell exhaustion markers (PD-1, CTLA-4, and TIM3), and lower expression of PD-L1 on tumour cells (Koyama et al, 2016a).”
Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma (2016, background): “424 Nevertheless, we could also discover a fact that TP53 mutation equally enhanced some other 425 non-PD-L1 immune inhibitory checkpoints expression, such as TIM-3 and VTCN1, which 426 might serve as potential primary resistance to TP53 mutation patients treated with 427 anti-PD-1/PD-L1(41).”
Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer (2017, background): “Indeed, upregulation of the immune inhibitory receptor TIM-3 on T-cells has been described to contribute to adaptive resistance to PD-1 blockade in mouse models and patient specimens (45).”
Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer (2016, methodology): “Although we were precluded from evaluating other immune modulators due to limited biopsy specimens, it is conceivable that transcriptomic signatures (31) or specific co-inhibitory factors, such as LAG-3 or T-cell immunoglobulin mucin-3 (TIM-3) (12), may play a role in immune checkpoint regulation.”
CDK4/6 Inhibition Augments Anti-Tumor Immunity by Enhancing T Cell Activation (2017, background): “The digested NFATc3 and His-GB1 were separated and further purified using size exclusion chromatography (GE Healthcare Life Sciences “Superdex 75 10/300 GL”).”