An Endogenous Retrovirus Vaccine Encoding an Envelope with a Mutated Immunosuppressive Domain in Combination with Anti-PD1 Treatment Eradicates Established Tumours in Mice
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Endogenous retroviruses (ERVs) account for 8% of our genome, and, although they are usually silent in healthy tissues, they become reactivated and expressed in pathological conditions such as cancer. Several studies support a functional role of ERVs in tumour development and progression, specifically through their envelope (Env) protein, which contains a region described as an immunosuppressive domain (ISD). We have previously shown that targeting of the murine ERV (MelARV) Env using virus-like vaccine (VLV) technology, consisting of an adenoviral vector encoding virus-like particles (VLPs), induces protection against small tumours in mice. Here, we investigate the potency and efficacy of a novel MelARV VLV with a mutated ISD (ISDmut) that can modify the properties of the adenoviral vaccine-encoded Env protein. We show that the modification of the vaccine’s ISD significantly enhanced T-cell immunogenicity in both prime and prime-boost vaccination regimens. The modified VLV in combination with an α-PD1 checkpoint inhibitor (CPI) exhibited excellent curative efficacy against large established colorectal CT26 tumours in mice. Furthermore, only ISDmut-vaccinated mice that survived CT26 challenge were additionally protected against rechallenge with a triple-negative breast cancer cell line (4T1), showing that our modified VLV provides cross-protection against different tumour types expressing ERV-derived antigens. We envision that translating these findings and technology into human ERVs (HERVs) could provide new treatment opportunities for cancer patients with unmet medical needs.
Originalsprog | Engelsk |
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Artikelnummer | 926 |
Tidsskrift | Viruses |
Vol/bind | 15 |
Udgave nummer | 4 |
Antal sider | 26 |
ISSN | 1999-4915 |
DOI | |
Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
The study was funded by InProTher ApS and within kind contribution from Sirion Biotech GmbH. Innovation Fund Denmark supported the realization of this project with granting a scholarship (9065-00055B) to Joana Daradoumis.
Publisher Copyright:
© 2023 by the authors.
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