Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts.
Cancer Res Commun. 2024 Feb 22;4(2):496-504. doi: 10.1158/2767-9764.CRC-23-0244.
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-A0201. 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-A0201 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.
雌激素受体阳性（ER+）乳腺癌被认为不具有免疫原性，迄今为止，已被证明对免疫疗法具有抗性。内分泌治疗仍然是 ER+乳腺癌治疗的基石。然而，雌激素受体 alpha（ESR1）基因中的组成性激活突变在治疗过程中可能会出现，从而使肿瘤对内分泌治疗产生抗性。尽管这些突变代表了一种抗性途径，但它们也代表了潜在的新抗原来源，可以通过免疫疗法来靶向。在这项研究中，我们研究了 ESR1 突变作为乳腺癌免疫治疗的新靶标。使用机器学习算法，我们鉴定了预测与 HLA-A0201 形成稳定复合物的 ESR1 衍生肽。然后，我们通过体外结合和解离测定验证了顶级预测肽的结合亲和力和稳定性，并表明这些肽与 HLA-A0201 具有高亲和力和稳定性。使用四聚体测定，我们证实了来自健康女性供体的抗原特异性 CTL 的存在和扩增潜力。最后，我们通过体外细胞毒性测定，显示了由扩展的抗原特异性 CTL 对表达常见 ESR1 突变的肽脉冲靶标和乳腺癌细胞的裂解。最终，我们鉴定了五个来自三种最常见 ESR1 突变（D538G、Y537S 和 E380Q）及其相关野生型肽的肽，它们具有最强的免疫原性。总体而言，这些数据证实了源自 ESR1 的表位的免疫原性，并强调了这些肽作为新型免疫治疗策略的靶标的潜力。
雌激素受体（ESR1）突变已成为内分泌治疗耐药的关键因素。我们鉴定并验证了五个新的、免疫原性的 ESR1 衍生肽，这些肽可以通过疫苗为基础的免疫疗法来靶向。
