Data from Endocrine therapy synergizes with SMAC mimetics to potentiate antigen presentation and tumor regression in hormone receptor-positive breast cancer
Year: 2024
Type: other
Abstract: 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.
Authors: Francisco Hermida-Prado, Yingtian Xie, Shira Sherman, Zsuzsanna Nagy, Douglas Russo, Tara Akhshi, Zhengtao Chu, Avery Feit, Marco Campisi, Minyue Chen, Agostina Nardone, Cristina Guarducci, Klothilda Lim, Alba Font-Tello, Irene Lee, Juana García-Pedrero, Israel Canadas, Judith Agudo, Ying Huang, Tal Sella, Qingchun Jin, Nabihah Tayob, Elizabeth A. Mittendorf, Sara M. Tolaney, Xintao Qiu, Henry Long, William F. Symmans, Jia-Ren Lin, Sandro Santagata, Isabelle Bedrosian, Denise A. Yardley, Ingrid A. Mayer, Edward T. Richardson, Giacomo Oliveira, Catherine J. Wu, Eugene F. Schuster, Mitch Dowsett, Alana L. Welm, David Barbie, Otto Metzger, Rinath Jeselsohn
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4402803111