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An ESR1 neoepitope vaccine targeting resistance mutations induces cross-protective anti-tumor immune responses against ER+ Breast Cancer

ABSTRACT: Estrogen receptor α (ER) positivity defines ~75% of breast cancers (BCs), treated with a variety of estrogen-targeting therapies. However, ~25% of patients with localized disease and nearly all metastatic disease patients develop resistance to such therapies. One major mechanism of resistance occurs through gain-of-function mutations in the gene encoding ER (ESR1), which occurs after prolonged endocrine therapy. These gain-of-function mutations render ESR1 constitutively active and represent critical neoepitopes of ER+ BC. We here confirm that these mutations permit ligand-independent estrogen signaling, as well as stimulate alternate pathways to enhance BC oncogenicity in vivo. As these oncogenic ESR1-mutated genes (ESR1mut) may be a significant, predictable contributor to the development of acquired resistance to endocrine therapy, we explored the potential of vaccination targeting these neoepitopes. In our study, we confirmed that these peptides are presented by MHC complexes and capable of stimulating CD8+ T-cell responses. Using recombinant adenoviral vectors encoding ESR1mut, we also demonstrate the induction of ESR1-specific immunity to generate anti-tumor responses against ESR1mut-expressing BC. Finally, we improved the safety profile, ESR1-specific immunity and anti-tumor efficacy of our vaccines using c-terminal subunit ESR1mut targeting, which has the potential to prevent the outgrowth of resistant ER+ BCs and improve patient outcomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE153033 | GEO | 2024/02/14

REPOSITORIES: GEO

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Project description:Abstract Several endocrine therapy (ET) resistance mechanisms for ER-positive (ER+) breast cancer (BC) have been proposed, including acquired ESR1 (ERα gene) mutations. The two most common ESR1 mutations are Y537S and D538G, which give rise to a constitutively active receptor with reduced affinity for agonists and antagonists. The discovery of new effective therapies remains a significant challenge in treating mutated ER+ BC. In this context, Poly (ADP-ribose) polymerase-1 (PARP-1) has captured considerable interest as a target for therapeutic inhibitors in specific types of cancers. Here, we report that crosstalk between PARP-1 and ERα may represent a novel therapeutic approach for ER+ BC. We have demonstrated that the up-regulation of PARP-1 expression, stimulated by 17-β estradiol (E2), was blocked by treatment with fulvestrant (Ful), a potent ERα antagonist, or ESR1 siRNA in ER+ MCF7 and T47D BC cell models that express both wild type ERα and the Y537S mutation, indicating that ERα regulates the expression of PARP-1. In addition, ERα-mediated transcriptional activity depended on PARP-1 activity in these models, as confirmed by ERα target gene expression and ERE reporter gene analyses +/- niraparib (Nira). Notably, PARP-1 modulates the estrogen-dependent genomic binding of ERα and FoxA1, which play a crucial role in the proliferation of ER+ BC. We also showed that PARP-1 inhibition prevented proliferation and cell cycle activities of ERα WT and ERα Y537S cells upon ERα activation. In vivo, Nira and lasofoxifene (Laso), an ERα antagonist, significantly reduced primary tumor growth versus vehicle, both as single agents and in combination. Moreover, RNA-seq analyses demonstrated the downregulation of ERα signaling in the mammary glands of mice treated with Nira versus Vehicle. Our results provide novel insights into the molecular events through which PARP-1 may serve as a more comprehensive therapeutic approach to target ET BC resistance in women with advanced ER+ BC.

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An ESR1 neoepitope vaccine targeting resistance mutations induces cross-protective anti-tumor immune responses against ER+ Breast Cancer

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