Journal article
Everolimus combined with PD-1 blockade inhibits progression of triple-negative breast cancer
Cellular signalling, Vol.109, p.110729
09/2023
DOI: 10.1016/j.cellsig.2023.110729
PMID: 37257766
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Due to rapid progression and a lack of targetable receptors, TNBC is exceptionally difficult to treat. Available treatment options are nonspecific cytotoxic agents, which have had modest success; thus, there is a need for novel therapies for TNBC. The mammalian/mechanistic target of rapamycin (mTOR) signaling pathway is aberrantly activated in TNBC, and this pathway has been shown to promote cancer cell survival and chemoresistance. As such, mTOR inhibition has been considered a potential therapeutic strategy for TNBC. The mTOR inhibitor everolimus (EVE) has been approved for the treatment of estrogen positive breast cancer; however, its efficacy in TNBC is still undetermined. In this study, we evaluated the effects of EVE monotherapy and the mechanism of EVE resistance in the 4T1 model of TNBC. Whereas EVE monotherapy inhibited mTOR signaling activity, it did not attenuate tumor progression. Additionally, tumors from EVE-treated mice had abnormal vasculature characterized by disorganized architecture and hyperpermeability. We also found that treatment with EVE increased PD-L1 expression in intratumoral vascular endothelial cells, and this increase in endothelial cell-associated PD-L1 corresponded to reduced CD8 + T cell tumor infiltration. Importantly, combination treatment with anti-PD-1 antibody and EVE normalized the tumor vasculature, rescued CD8 + T cell tumor infiltration, and reduced tumor growth. Taken together, our findings improve our current understanding of mechanisms underlying mTOR inhibition resistance in TNBC and identify a novel combination treatment strategy in the treatment of mTOR resistant tumors.
•Discovered a novel mechanism that explains the resistance of TNBC to everolimus monotherapy.•Discovered the function of anti-PD-1 plus everolimus in vascular normalization and immune infiltration in TNBC.•Proved the principle of combining anti-PD-1 and everolimus in treating TNBCs.
Details
- Title: Subtitle
- Everolimus combined with PD-1 blockade inhibits progression of triple-negative breast cancer
- Creators
- Guangxin Li - Peking University Shenzhen HospitalJiajia Hu - Ruijin HospitalChristina Cho - Yale UniversityJunwei Cui - Peking University Shenzhen HospitalAo Li - Yale UniversityPengwei Ren - Yale UniversityJichun Zhou - Sir Run Run Shaw HospitalWei Wei - Peking University Shenzhen HospitalTianxiang Zhang - Yale UniversityXiaoling Liu - Peking University Shenzhen HospitalWeiru Liu - University of Pennsylvania
- Resource Type
- Journal article
- Publication Details
- Cellular signalling, Vol.109, p.110729
- DOI
- 10.1016/j.cellsig.2023.110729
- PMID
- 37257766
- NLM abbreviation
- Cell Signal
- ISSN
- 0898-6568
- eISSN
- 1873-3913
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 09/2023
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984949218202771
Metrics
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