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

Reem Saleh, Salman M. Toor, Dana Al-Ali, Varun Sasidharan Nair, Eyad Elkord*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number703
Pages (from-to)1-17
Number of pages17
JournalGenes
Volume11
Issue number6
DOIs
Publication statusPublished - Jun 2020
Externally publishedYes

Keywords

  • Immune checkpoint inhibitors
  • Immune responses
  • Primary breast cancer
  • Transcriptomic profiling

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