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Redirecting host preexisting influenza A virus immunity for cancer immunotherapy

ABSTRACT: We tested the concept that host preexisting influenza A virus immunity can be redirected to inhibit tumor growth and metastasis through systemic administration of influenza A virus–related peptides to targeted tumors. Mice infected with influenza A virus strain A/Puerto Rico/8/34 (PR8) were used as a model of a host with preexisting viral immunity. The extent to which preexisting influenza A immunity in PR8-immunized mice can be redirected to inhibit tumor growth and metastasis was first examined by ectopic expression of influenza A nucleoprotein (NP) and hemagglutinin (HA) in syngeneic mammary tumor cells via lentiviral transduction. Then, the feasibility of implementing this strategy using a systemic therapy approach was assessed by systemic delivery of major histocompatibility complex class I (MHC-I)-compatible peptides to targeted mammary tumors overexpressing human epidermal growth factor receptor-2 (HER2) in mice using a novel HER2-targeting single-lipid nanoparticle (SLNP). Our results show that preexisting influenza A immunity in PR8-immunized mice could be quickly redirected to syngeneic tumors expressing influenza A NP and HA, leading to strong inhibition of tumor growth and metastasis and improvement of survival compared to the findings in antigen-naïve control mice. MHC-I-compatible peptides could be delivered to targeted mammary tumors in mice using the HER2-targeting SLNP for antigen presentation, which subsequently redirected preexisting influenza A immunity to the tumors to exert antitumor activities. In conclusion, preexisting influenza A immunity can be repurposed for cancer immunotherapy through systemic delivery of influenza A–related peptides to targeted tumors. Further development of the strategy for clinical translation is warranted.

SUBMITTER: Chaganty B

PROVIDER: S-EPMC8563826 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In pandemic scenarios involving novel human pathogenic viruses, it is highly desirable that vaccines induce strong neutralizing antibodies as quickly as possible. However, current vaccine strategies require multiple immunization doses to produce high titers of neutralizing antibodies and are poorly protective after a single vaccination. We therefore wished to design a vaccine candidate that would induce increased protective immune responses following the first vaccine dose. We hypothesized that antibodies against the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein could be increased by drawing upon immunity to a previous infection. We generated a fusion protein containing the influenza H1N1 PR8 virus nucleoprotein (NP) and the SARS-CoV-2 spike RBD. Mice with or without preexisting immunity to PR8 were then vaccinated with NP/RBD. We observed significantly increased SARS-CoV-2 neutralizing antibodies in mice with PR8 immunity compared to mice without preexisting PR8 immunity. Vaccination with NP/RBD protected mice from SARS-CoV-2-induced morbidity and mortality after a single dose. Additionally, we compared SARS-CoV-2 virus titers in the lungs and nasal turbinates 4 days post-challenge of mice vaccinated with NP/RBD. SARS-CoV-2 virus was detectable in the lungs and nasal turbinate of mice without preexisting PR8 immunity, while SARS-CoV-2 virus was completely undetectable in mice with preexisting PR8 immunity. We also found that CD4-positive T cells in mice with preexisting immunity to PR8 play an essential role in producing the increased antibody response against RBD. This vaccine strategy potentially can be modified to target other pathogens of concern and offers extra value in future pandemic scenarios.IMPORTANCEIncreased globalization and changes in human interactions with wild animals has increased the likelihood of the emergence of novel viruses with pandemic potential. Vaccines can be effective in preventing severe disease caused by pandemic viruses. However, it takes time to develop protective immunity via prime-boost vaccination. More effective vaccine designs should quickly induce protective immunity. We propose leveraging preexisting immunity to a different pathogen to boost protection against emerging viruses. We targeted SARS-CoV-2 as a representative pandemic virus and generated a fusion protein vaccine that combines the nucleoprotein from influenza A virus and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Our vaccine design significantly increased the production of RBD-specific antibodies in mice that had previously been exposed to influenza virus, compared to those without previous exposure. This enhanced immunity reduced SARS-CoV-2 replication in mice. Our results offer a vaccine design that could be valuable in a future pandemic setting.

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Redirecting host preexisting influenza A virus immunity for cancer immunotherapy

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