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FIGURE 1 from Estrogen Receptor Mutations as Novel Targets for Immunotherapy in Metastatic Estrogen Receptor–positive Breast Cancer

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posted on 2024-02-22, 14:40 authored by Jonathan Goldberg, Na Qiao, Jennifer L. Guerriero, 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. Mittendorf

Peptides bind to HLA-A*0201. T2 cells were pulsed with indicated peptide for 4 hours and surface HLA-A*0201 was stained. MFI of pulsed T2 cells were normalized to experimentally matched non-pulsed T2 cells, and data expressed as fold change in MFI. Dashed horizontal line indicates non-pulsed T2 HLA-A*0201. FLU peptide was used as a positive control HLA-A*0201 peptide known to bind with high affinity. Data represent three independent experiments performed in triplicate. Statistical significance was determined via comparison of pulsed MFI versus non-pulsed raw MFI using unpaired Student t test. ***, P < 0.001.

Funding

Parker Institute for Cancer Immunotherapy (PICI)

Rob and Karen Hale

HMS | Ludwig Center at Harvard (Ludwig Center)

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ARTICLE ABSTRACT

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

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