Background and Premise: Triple-negative breast cancer (TNBC) is an aggressive, metastatic disease with high mortality. The standard-of-care neoadjuvant chemotherapy (NACT) shows an initial response but followed by a drug resistance, increase in tumor relapse and distant metastases. Immunotherapy against programmed death ligand-1 (PD-L1) has shown efficacy in treating a subset of TNBC patients. However, it shows resistance in other patients due to new immune checkpoints such as VISTA, TIGIT, and LAG3. 

eIF4A1 is a mRNA helicase known to translate many oncogenic mRNAs including survivin, c-MYC, ROCK1, STAT1, ARF6 etc., We previously established that eIF4A1 is a vulnerable target in drug-resistant TNBC. Interestingly, we observed a reduction in levels of PD-L1 when eIF4A1 is targeted. Many downstream effectors of eIF4A1 such as c-MYC, STAT1 and ARF6 are indeed upstream regulators of PD-L1. This premise formed the basis to co-target eIF4A1 and PD-L1. Before that, we need to establish the clinical relevance of these targets in human TNBC biospecimens. This will ascertain the differential operation of the eIF4A1-PD-L1 axis in therapy-naïve and drug-resistant primary and mTNBC.

Approach: Human biospecimens obtained from CHTN NIH repositories (more than 100 TNBC primary tumor and metastatic biospecimens) will be analyzed for role of eIF4A1 in translation of oncogenic mRNAs that contribute to PD-L1 and other emerging immune checkpoint markers such as VISTA, TIGIT, and LAG3 via immunohistochemistry (after deglycosylation for effective detection of PD-L1) and also by immunoblotting. 

Results: The levels of total eIF4A1 from 16 matched, therapy naive TNBC tissue were compared to adjacent normal breast tissue from the same patient via immunoblotting. Total eIF4A1 levels were found to be significantly elevated in TNBC compared to adjacent normal tissue. The downstream effectors of eIF4A1 such as STAT1 and ARF6 were also significantly elevated indicating a robust helicase activity of eIF4A1. Importantly, PD-L1 levels was found to be elevated. Additionally, the total eIF4A1 level were elevated in drug-resistant tumors than normal breast tissue samples as assesses by immunohistochemistry. 

Conclusion: The eIF4A1-STAT1-PD-L1 axis is highly active in TNBC especially in drug-resistant situations. Currently, we are evaluating other immune checkpoints such as VISTA, TIGIT, and LAG3. 


Operation of eIF4A1-PD-L1 axis in therapy-naïve and drug-resistant TNBC

Basic Science | Hematology / Oncology / Pathology

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Operation of eIF4A1-PD-L1 axis in therapy-naïve and drug-resistant TNBC

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