دورية أكاديمية
Endocrine Therapy Synergizes with SMAC Mimetics to Potentiate Antigen Presentation and Tumor Regression in Hormone Receptor-Positive Breast Cancer.
| العنوان: | Endocrine Therapy Synergizes with SMAC Mimetics to Potentiate Antigen Presentation and Tumor Regression in Hormone Receptor-Positive Breast Cancer. |
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| المؤلفون: | 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 |
| المساهمون: | Schuster, Eugene |
| بيانات النشر: | AMER ASSOC CANCER RESEARCH |
| سنة النشر: | 2023 |
| المجموعة: | The Institute of Cancer Research (ICR): Publications Repository |
| جغرافية الموضوع: | United States |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | Print-Electronic; CAN-23-1711 -; application/pdf |
| اللغة: | English |
| تدمد: | 0008-5472 1538-7445 |
| العلاقة: | 727814; Cancer Research, 2023, pp. CAN-23-1711 -; https://repository.icr.ac.uk/handle/internal/5995Test |
| DOI: | 10.1158/0008-5472.CAN-23-1711 |
| الإتاحة: | https://doi.org/10.1158/0008-5472.CAN-23-1711Test https://repository.icr.ac.uk/handle/internal/5995Test |
| حقوق: | http://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: | edsbas.955FBA76 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 00085472 15387445 |
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| DOI: | 10.1158/0008-5472.CAN-23-1711 |