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Biomimetic nanoparticles deliver mRNAs encoding costimulatory receptors and enhance T cell mediated cancer immunotherapy.

ABSTRACT: Antibodies targeting costimulatory receptors of T cells have been developed for the activation of T cell immunity in cancer immunotherapy. However, costimulatory molecule expression is often lacking in tumor-infiltrating immune cells, which can impede antibody-mediated immunotherapy. Here, we hypothesize that delivery of costimulatory receptor mRNA to tumor-infiltrating T cells will enhance the antitumor effects of antibodies. We first design a library of biomimetic nanoparticles and find that phospholipid nanoparticles (PL1) effectively deliver costimulatory receptor mRNA (CD137 or OX40) to T cells. Then, we demonstrate that the combination of PL1-OX40 mRNA and anti-OX40 antibody exhibits significantly improved antitumor activity compared to anti-OX40 antibody alone in multiple tumor models. This treatment regimen results in a 60% complete response rate in the A20 tumor model, with these mice being resistant to rechallenge by A20 tumor cells. Additionally, the combination of PL1-OX40 mRNA and anti-OX40 antibody significantly boosts the antitumor immune response to anti-PD-1 + anti-CTLA-4 antibodies in the B16F10 tumor model. This study supports the concept of delivering mRNA encoding costimulatory receptors in combination with the corresponding agonistic antibody as a strategy to enhance cancer immunotherapy.

SUBMITTER: Li W

PROVIDER: S-EPMC8671507 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Biomimetic nanoparticles deliver mRNAs encoding costimulatory receptors and enhance T cell mediated cancer immunotherapy.

Li Wenqing W Zhang Xinfu X Zhang Chengxiang C Yan Jingyue J Hou Xucheng X Du Shi S Zeng Chunxi C Zhao Weiyu W Deng Binbin B McComb David W DW Zhang Yuebao Y Kang Diana D DD Li Junan J Carson William E WE Dong Yizhou Y

Nature communications 20211214 1

Antibodies targeting costimulatory receptors of T cells have been developed for the activation of T cell immunity in cancer immunotherapy. However, costimulatory molecule expression is often lacking in tumor-infiltrating immune cells, which can impede antibody-mediated immunotherapy. Here, we hypothesize that delivery of costimulatory receptor mRNA to tumor-infiltrating T cells will enhance the antitumor effects of antibodies. We first design a library of biomimetic nanoparticles and find that p ...[more]

PMID: 34907171

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Project description:Lipid nanoparticle (LNP)-encapsulated mRNAs have emerged as effective vaccination tools to stimulate immunity. The most common application of this technology is to deliver mRNAs that encode antigenic proteins to dendritic cells (DCs), which then stimulate antigen-specific lymphocyte responses. It is unclear whether other immunostimulatory DC activities necessary for vaccine efficacy, beyond antigen presentation, can be induced via mRNA-encoded proteins. Herein, we report an mRNA encoding a self-DNA reactive variant of the enzyme cyclic GMP-AMP synthase (cGAS), known as cGAS∆N. cGAS∆N produces the cyclic dinucleotide cGAMP upon binding intra-mitochondrial DNA. cGAMP binds the protein STING, which activates innate immune responses that stimulate T cells. We found that when delivered to DCs via LNPs, mRNA-encoded cGAS∆N induced the upregulation of chemokine receptors, T cell costimulatory molecules, major histocompatibility complex proteins, pro-inflammatory cytokines and type I interferons from murine and human DCs. These activities exceeded the immunostimulatory activities of mRNA-encoded antigens delivered via LNPs. Co-immunization of mice with antigen-LNPs and cGAS∆N-LNPs led to the robust production of antigen-specific IFNγ-producing T cells. These T cell responses were durable and circulated through the lymphatics, blood, and lungs. Immunizations with antigen-LNPs alone, akin to what are used in the clinic, stimulated weak and transient T cell responses. Antibody responses to antigen-LNPs were biased towards type I isotypes when co-injected with cGAS∆N-LNPs, as compared to immunizations with antigen-LNPs alone. These findings establish the enzyme cGAS∆N as a catalytic adjuvant, which may prove useful in enhancing the immunogenicity of nucleic acid-based vaccines. IMPORTANCE Nucleic acid-based vaccines hold promise in preventing infections and treating cancer. The most common use of this technology is to encode antigenic proteins on mRNAs that are delivered to cells via lipid nanoparticle (LNP) formulations. In this study, we discovered that immunostimulatory proteins can also be encoded on mRNAs in LNPs. We found that an active mutant of the enzyme cGAS, referred to as cGAS∆N, acts as a catalytic adjuvant in LNP-encapsulated mRNA vaccines. The delivery of cGAS∆N mRNA via LNPs in combination with antigen mRNA-LNPs led to durable antigen-specific IFNγ-producing T cells that exceeded the efficiency of antigen-LNPs similar to those currently used in the clinic. This strategy did not compromise B cell responses; rather it induced Th1-biased antibody isotypes. This work unveils new vaccine design strategies using mRNA-encoded catalytic adjuvants that could be ideal for generating CD8+ T cell and B cell responses for immunotherapies.

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Biomimetic nanoparticles deliver mRNAs encoding costimulatory receptors and enhance T cell mediated cancer immunotherapy.

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Biomimetic nanoparticles deliver mRNAs encoding costimulatory receptors and enhance T cell mediated cancer immunotherapy.

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