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

Autor:	Dailey GP; Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA., Rabiola CA; Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA., Lei G; Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA., Wei J; Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA., Yang XY; Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA., Wang T; Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA., Liu CX; Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA., Gajda M; Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA., Hobeika AC; Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA., Summers A; Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA., Marek RD; Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA., Morse MA; Department of Medicine, Duke University, Durham, NC, USA., Lyerly HK; Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA.; Department of Pathology, Duke University, Durham, NC, USA.; Department of Integrative Immunobiology, Duke University, Durham, NC, USA., Crosby EJ; Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA.; Department of Integrative Immunobiology, Duke University, Durham, NC, USA., Hartman ZC; Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA.; Department of Pathology, Duke University, Durham, NC, USA.; Department of Integrative Immunobiology, Duke University, Durham, NC, USA.
Jazyk:	angličtina
Zdroj:	Human vaccines & immunotherapeutics [Hum Vaccin Immunother] 2024 Dec 31; Vol. 20 (1), pp. 2309693. Date of Electronic Publication: 2024 Feb 08.
DOI:	10.1080/21645515.2024.2309693
Abstrakt:	ER+ breast cancers (BC) are characterized by the elevated expression and signaling of estrogen receptor alpha ( ESR1) , 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 ESR1 . The central importance of ESR1 and development of mutated forms of ESR1 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 ESR1 ( ESR1 mut) and validated their ability to elicit ESR1 -specific T cell responses. We then developed novel ESR1 mut-expressing murine mammary cancer models to test the anti-tumor potential of ESR1 mut vaccines. We found that these vaccines could suppress tumor growth, ESR1 mut expression and estrogen signaling in vivo. To illustrate the applicability of these findings, we utilize HPLC to demonstrate the presentation of ESR1 and ESR1 mut peptides on human ER+ BC cell MHC complexes. We then show the presence of human T cells reactive to ESR1 mut epitopes in an ER+ BC patient. These findings support the development of ESR1 mut vaccines, which we are testing in a Phase I clinical trial.
Databáze:	MEDLINE
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