KEY TAKEAWAYS
- The study aimed to explore ESR1 mutations as potential targets for immunotherapy in breast cancer patients.
- The findings affirmed the immunogenicity of ESR1-derived epitopes, underscoring their potential as targets for innovative immunotherapy approaches.
Estrogen receptor-positive (ER+) breast cancer is traditionally viewed as non-immunogenic and typically resistant to immunotherapy. Endocrine therapy remains the primary treatment modality for ER+ breast cancers. However, the emergence of constitutively activating mutations in the estrogen receptor alpha (ESR1) gene during treatment can confer resistance to endocrine therapy. Despite serving as a mechanism of resistance, these mutations also present as potential neoepitopes, offering opportunities for targeted immunotherapy.
Jonathan Goldberg and his team aimed to explore ESR1 mutations as potential targets for immunotherapy in breast cancer.
The study utilized machine learning algorithms, ESR1-derived peptides with a predicted ability to form stable complexes with HLA-A* 0201 were identified. Validation of the top predicted peptides’ binding affinity and stability was conducted through in-vitro binding and dissociation assays, revealing high affinity and stability with HLA-A*0201. Tetramer assays confirmed the presence and expansion potential of antigen-specific cytotoxic T lymphocytes (CTLs) from healthy female donors.
In-vitro cytotoxicity assays demonstrated the lysis of peptide-pulsed targets and breast cancer cells expressing common ESR1 mutations by expanded antigen-specific CTLs. Ultimately, five peptides derived from the three most common ESR1 mutations (D538G, Y537S, and E380Q) and their associated wild-type peptides were identified as the most immunogenic.
These findings validated the immunogenicity of ESR1-derived epitopes and emphasize their promise as targets for novel immunotherapy strategies.
Source: https://pubmed.ncbi.nlm.nih.gov/38335301/
Goldberg J, Qiao N, Guerriero JL, et al. (2023)’’Estrogen Receptor Mutations as Novel Targets for Immunotherapy in Metastatic Estrogen Receptor-Positive Breast Cancer.’’ Cancer Res Commun. 2024 Feb 9. doi: 10.1158/2767-9764.CRC-23-0244. Epub ahead of print. PMID: 38335301.
