Exhausted T cell signature predicts immunotherapy response in ER-positive breast cancer.
Manuela Terranova-BarberioNela PawlowskaMallika DhawanMark M MoasserAmy J ChienMichelle E MeliskoHope RugoRoshun RahimiTravis DealAdil I DaudMichael D RosenblumScott ThomasPamela N MunsterPublished in: Nature communications (2020)
Responses to immunotherapy are uncommon in estrogen receptor (ER)-positive breast cancer and to date, lack predictive markers. This randomized phase II study defines safety and response rate of epigenetic priming in ER-positive breast cancer patients treated with checkpoint inhibitors as primary endpoints. Secondary and exploratory endpoints included PD-L1 modulation and T-cell immune-signatures. 34 patients received vorinostat, tamoxifen and pembrolizumab with no excessive toxicity after progression on a median of five prior metastatic regimens. Objective response was 4% and clinical benefit rate (CR + PR + SD > 6 m) was 19%. T-cell exhaustion (CD8+ PD-1+/CTLA-4+) and treatment-induced depletion of regulatory T-cells (CD4+ Foxp3+/CTLA-4+) was seen in tumor or blood in 5/5 patients with clinical benefit, but only in one non-responder. Tumor lymphocyte infiltration was 0.17%. Only two non-responders had PD-L1 expression >1%. This data defines a novel immune signature in PD-L1-negative ER-positive breast cancer patients who are more likely to benefit from immune-checkpoint and histone deacetylase inhibition (NCT02395627).
Keyphrases
- positive breast cancer
- estrogen receptor
- regulatory t cells
- histone deacetylase
- phase ii study
- open label
- endoplasmic reticulum
- end stage renal disease
- dendritic cells
- breast cancer cells
- placebo controlled
- newly diagnosed
- ejection fraction
- double blind
- squamous cell carcinoma
- randomized controlled trial
- gene expression
- clinical trial
- chronic kidney disease
- cell cycle
- dna damage
- peritoneal dialysis
- oxidative stress
- prognostic factors
- phase iii
- genome wide
- body mass index
- study protocol
- locally advanced
- radiation therapy
- weight loss
- tyrosine kinase
- drug induced
- combination therapy
- patient reported
- endothelial cells