Endocrine Therapy Synergizes with SMAC Mimetics to Potentiate Antigen Presentation and Tumor Regression in Hormone Receptor-Positive Breast Cancer.
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Date
2023-10-02ICR Author
Author
Hermida-Prado, F
Xie, Y
Sherman, S
Nagy, Z
Russo, D
Akhshi, T
Chu, Z
Feit, A
Campisi, M
Chen, M
Nardone, A
Guarducci, C
Lim, K
Font-Tello, A
Lee, I
García-Pedrero, J
Cañadas, I
Agudo, J
Huang, Y
Sella, T
Jin, Q
Tayob, N
Mittendorf, EA
Tolaney, SM
Qiu, X
Long, H
Symmans, WF
Lin, J-R
Santagata, S
Bedrosian, I
Yardley, DA
Mayer, IA
Richardson, ET
Oliveira, G
Wu, CJ
Schuster, EF
Dowsett, M
Welm, AL
Barbie, D
Metzger, O
Jeselsohn, R
Type
Journal Article
Metadata
Show full item recordAbstract
UNLABELLED: 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 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 β2-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 blocks prosurvival effects of NF-κB signaling through the degradation of inhibitors of apoptosis proteins, elicited tumor regression through cell autonomous mechanisms, providing additional support for their combined use in HR+ breast cancer. SIGNIFICANCE: Adding SMAC mimetics to endocrine therapy enhances tumor regression in a cell autonomous manner while increasing tumor immunogenicity, indicating that this combination could be an effective treatment for HR+ patients with breast cancer.
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Research team
Endocrine Therapy Resist
Endocrinology
Language
eng
Date accepted
2023-07-12
License start date
2023-07-14
Citation
Cancer Research, 2023, pp. CAN-23-1711 -
Publisher
AMER ASSOC CANCER RESEARCH