Faculty, Staff and Student Publications
Publication Date
10-2-2023
Journal
Cancer Research
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 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.
Keywords
Humans, Female, NF-kappa B, Intracellular Signaling Peptides and Proteins, Breast Neoplasms, Antigen Presentation, Apoptosis Regulatory Proteins, Apoptosis, Cell Line, Tumor, Mitochondrial Proteins, Tumor Microenvironment
DOI
10.1158/0008-5472.CAN-23-1711
PMID
37450351
PMCID
PMC10543960
PubMedCentral® Posted Date
7-14-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons