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Blockade of PD-1, PD-L1, and TIM-3 Altered Distinct Immune- and Cancer-Related Signaling Pathways in the Transcriptome of Human Breast Cancer Explants

1
Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha 34110, Qatar
2
Department of Medicine, Weil Cornell Medicine-Qatar, Doha 24144, Qatar
*
Author to whom correspondence should be addressed.
Authors contributed equally to this work.
Genes 2020, 11(6), 703; https://doi.org/10.3390/genes11060703
Received: 21 May 2020 / Revised: 15 June 2020 / Accepted: 21 June 2020 / Published: 25 June 2020
(This article belongs to the Section Human Genomics and Genetic Diseases)
Immune checkpoint inhibitors (ICIs) are yet to have a major advantage over conventional therapies, as only a fraction of patients benefit from the currently approved ICIs and their response rates remain low. We investigated the effects of different ICIs—anti-programmed cell death protein 1 (PD-1), anti-programmed death ligand-1 (PD-L1), and anti-T cell immunoglobulin and mucin-domain containing-3 (TIM-3)—on human primary breast cancer explant cultures using RNA-Seq. Transcriptomic data revealed that PD-1, PD-L1, and TIM-3 blockade follow unique mechanisms by upregulating or downregulating distinct pathways, but they collectively enhance immune responses and suppress cancer-related pathways to exert anti-tumorigenic effects. We also found that these ICIs upregulated the expression of other IC genes, suggesting that blocking one IC can upregulate alternative ICs, potentially giving rise to compensatory mechanisms by which tumor cells evade anti-tumor immunity. Overall, the transcriptomic data revealed some unique mechanisms of the action of monoclonal antibodies (mAbs) targeting PD-1, PD-L1, and TIM-3 in human breast cancer explants. However, further investigations and functional studies are warranted to validate these findings. View Full-Text
Keywords: primary breast cancer; transcriptomic profiling; immune checkpoint inhibitors; immune responses primary breast cancer; transcriptomic profiling; immune checkpoint inhibitors; immune responses
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Saleh, R.; Toor, S.M.; Al-Ali, D.; Sasidharan Nair, V.; Elkord, E. Blockade of PD-1, PD-L1, and TIM-3 Altered Distinct Immune- and Cancer-Related Signaling Pathways in the Transcriptome of Human Breast Cancer Explants. Genes 2020, 11, 703.

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