Estrogen Receptor Mutations as Novel Targets for Immunotherapy in Metastatic Estrogen Receptor–positive Breast Cancer

• DOI: 10.1158/2767-9764.crc-23-0244
• Publication Date: 2024-02-09T19:12:10Z
• Authors: Jonathan Goldberg; Na Qiao; Jennifer L. Guerr...; Brett Gross; Yagiz Meneksedag; Yoshimi F. Lu; Anne V. Philips; Tasnim Rahman; Funda Meric-Bernstam; Jason Roszik; Ken Chen; Rinath Jeselsohn; Sara M. Tolaney; George E. Peoples; Gheath Alatrash; Elizabeth A. Mitt...
• Keywords: Estrogen receptor alpha; Cancer Immunotherapy

Abstract Estrogen receptor–positive (ER+) breast cancer is not considered immunogenic and, to date, has been proven resistant immunotherapy. Endocrine therapy remains the cornerstone of treatment for ER+ cancers. However, constitutively activating mutations in estrogen receptor alpha (ESR1) gene can emerge during treatment, rendering tumors endocrine therapy. Although these represent a pathway resistance, they also potential source neoepitopes that be targeted by In this study, we investigated ESR1 as novel targets Using machine learning algorithms, identified ESR1-derived peptides predicted form stable complexes with HLA-A*0201. We then validated binding affinity and stability top through vitro dissociation assays showed bind HLA-A*0201 high stability. tetramer assays, confirmed presence expansion antigen-specific CTLs from healthy female donors. Finally, using cytotoxicity lysis peptide-pulsed cells expressing common expanded CTLs. Ultimately, five derived three most (D538G, Y537S, E380Q) their associated wild-type peptides, which were immunogenic. Overall, data confirm immunogenicity epitopes highlight immunotherapy strategies. Significance: have emerged key factor resistance. novel, could vaccine-based