Endocrine therapy synergizes with SMAC mimetics to potentiate antigen presentation and tumor regression in hormone receptor-positive breast cancer.
Francisco Hermida-PradoYingtian XieShira ShermanZsuzsanna NagyDouglas RussoTara AkhshiZhengtao ChuAvery FeitMarco CampisiMinyue ChenAgostina NardoneCristina GuarducciKlothilda LimAlba Font-TelloIrene I LeeJuana María García-PedreroIsrael CañadasJudith AgudoYing HuangTal SellaQingchun JinNabihah TayobElizabeth A MittendorfSara M TolaneyXintao QiuHenry W LongWilliam Fraser SymmansJia-Ren LinSandro SantagataIsabelle BedrosianDenise A YardleyIngrid A MayerEdward T RichardsonGiacomo OliveiraCatherine J WuEugene F SchusterMitchell DowsettAlana L WelmDavid A BarbieOtto Metzger FilhoRinath M JeselsohnPublished in: Cancer research (2023)
Immunotherapies have yet to demonstrate significant efficacy in the treatment of hormone receptor positive (HR+) breast cancer. Given that endocrine therapy (ET) is the primary approach for treating HR+ breast cancer, we investigated the effects of ET on the tumor immune microenvironment (TME) in HR+ breast cancer. Spatial proteomics analysis of primary HR+ breast cancer samples obtained at baseline and after ET from patients enrolled in a neoadjuvant clinical trial (NCT02764541) indicated that ET upregulated B2-microglobulin and influenced the TME in a manner that promotes enhanced immunogenicity. To gain a deeper understanding of the underlying mechanisms, the intrinsic effects of ET on cancer cells were explored, which revealed that ET plays a crucial role in facilitating the chromatin binding of RelA, a key component of the NF-κB complex. Consequently, heightened NF-κB signaling enhanced the response to interferon-gamma, leading to the upregulation of β2-microglobulin and other antigen presentation-related genes. Further, modulation of NF-κB signaling using a SMAC-mimetic in conjunction with ET augmented T-cell migration and enhanced MHC-I specific T-cell mediated cytotoxicity. Remarkably, the combination of ET and SMAC-mimetics, which also block pro-survival effects of NF-κB signaling through the degradation of inhibitors of apoptosis (IAP) proteins, elicited tumor regression through cell-autonomous mechanisms, providing additional support for their combined use in HR+ breast cancer.
Keyphrases
- signaling pathway
- oxidative stress
- lps induced
- clinical trial
- cell migration
- end stage renal disease
- positive breast cancer
- nuclear factor
- gene expression
- chronic kidney disease
- stem cells
- ejection fraction
- dna damage
- randomized controlled trial
- mass spectrometry
- squamous cell carcinoma
- cell death
- lymph node
- transcription factor
- dendritic cells
- prognostic factors
- peritoneal dialysis
- case report
- poor prognosis
- endoplasmic reticulum stress
- long non coding rna
- genome wide
- replacement therapy
- virtual reality
- phase ii
- placebo controlled