Description:
<jats:title>Abstract</jats:title>
<jats:p>Cowpea mosaic virus (CPMV), a non-enveloped plant virus, and empty CPMV (eCPMV), a virus-like particle composed of CPMV capsid, have demonstrated strong activation of neutrophils, suppression of primary tumor growth, and durable systemic antitumor immunity in murine models with no side effects when administered intratumorally as an in situ vaccine. However, it is not known how immune cells recognize these nanoparticles. In this study, CPMV and eCPMV exhibited overlapping yet distinctive recognition patterns and immunostimulatory profiles. Specifically, CPMV generated stronger selective induction of cytokines and chemokines in naive splenocytes and exhibited more potent antitumor efficacy compared to eCPMV. We found that MyD88 is required for both CPMV- and eCPMV-elicited immune responses. Screening with HEK-BlueTM mouse and human Toll-like receptor (TLR) assays along with response and efficacy studies in corresponding TLR-/- mice indicated the recognition of both CPMV and eCPMV by MyD88-dependent TLR2 and TLR4 as well as recognition of CPMV by TLR7. Furthermore, the studies revealed that TLR2 and TLR4 are complementary to each other in recognizing the capsid of either particle in vivo and in vitro. We further confirmed that secretion of type I interferons (IFNs) by CPMV is critical to its stronger efficacy, which is dependent on the binding between TLR7 and the encapsulated single-stranded RNAs (ssRNAs) of CPMV. These findings link efficacy with molecular recognition and provide rationale for developing more potent viral particles as immunotherapeutic vaccines to cancer.</jats:p>
<jats:p>Citation Format: Chenkai Mao, Veronique Beiss, Sourabh Shukla, Nicole Steinmetz, Steven Fiering. Cowpea mosaic virus stimulates antitumor immunity through recognition by MYD88-dependent signaling of multiple Toll-like receptors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B19.</jats:p>