Vaccines targeting <i>ESR1</i> activating mutations elicit anti-tumor immune responses and suppress estrogen signaling in therapy resistant ER+ breast cancer

ER+ breast cancers (BC) are characterized by the elevated expression and signaling of estrogen receptor alpha (<i>ESR1)</i>, which renders them sensitive to anti-endocrine therapy. While these therapies are clinically effective, prolonged treatment inevitably results in therapeutic resistance, which can occur through the emergence of gain-of-function mutations in <i>ESR1</i>. The central importance of <i>ESR1</i> and development of mutated forms of <i>ESR1</i> suggest that vaccines targeting these proteins could potentially be effective in preventing or treating endocrine resistance. To explore the potential of this approach, we developed several recombinant vaccines encoding different mutant forms of <i>ESR1</i> (<i>ESR1</i>mut) and validated their ability to elicit <i>ESR1</i>-specific T cell responses. We then developed novel <i>ESR1</i>mut-expressing murine mammary cancer models to test the anti-tumor potential of <i>ESR1</i>mut vaccines. We found that these vaccines could suppress tumor growth, <i>ESR1</i>mut expression and estrogen signaling in vivo. To illustrate the applicability of these findings, we utilize HPLC to demonstrate the presentation of <i>ESR1</i> and <i>ESR1</i>mut peptides on human ER+ BC cell MHC complexes. We then show the presence of human T cells reactive to <i>ESR1</i>mut epitopes in an ER+ BC patient. These findings support the development of <i>ESR1</i>mut vaccines, which we are testing in a Phase I clinical trial.