Date of Award
2022
Document Type
Thesis (Ph.D.)
Department or Program
Microbiology and Immunology
First Advisor
Steven Fiering
Abstract
Non-infectious to mammals, genetically, and physically stable plant virus-based nanoparticles have been increasingly studied as a novel platform for cancer vaccine and adjuvants due to their immunogenic properties. Our prior work showed that, empty cowpea mosaic virus (eCPMV), a plant virus-like particle (VLP) that is composed of a separated capsid, is an excellent in situ vaccine (ISV) for cancer immunotherapy; however, little is known about the mechanisms linked to their activities regarding recognition and antigen presentation.
In the present studies, we report cowpea mosaic virus (CPMV) and RNA-lacking CPMV (empty, eCPMV) are both toll like receptor (TLR) agonists for TLRs 2 and 4; CPMV is additionally recognized by TLR7. The same recognition mechanisms are also functional in human peripheral blood mononuclear cells (PBMCs). Furthermore, the strong recognition of CPMV by TLR 7 and its downstream induction of type I interferons (IFNs) may be the key contributor for the better efficacy of CPMV when compared with cowpea severe mosaic virus (CPSMV) and tobacco ring spot virus (TRSV), two other plant viruses from the secoviridae family. In addition, we found that conventional dendritic cell 1 (cDC1) and its cross-priming are crucial for the systemic efficacy of CPMV. We designed a powerful ISV combination of CPMV with anti-CD40. Along with systemic administration of anti-PD1, this new treatment regimen exhibited excellent efficacy in different immune cold tumors.
Overall, these findings link CPMV immunotherapy efficacy with molecular recognition and cross-priming, provide rationale for designing potent viral particles and treatment schemes, accentuate the value of multi-TLR agonists as in situ cancer vaccines, and highlight the importance of type I IFNs for in situ vaccination.
Original Citation
Mao C, Beiss V, Fields J, Steinmetz NF, Fiering S. Cowpea mosaic virus stimulates antitumor immunity through recognition by multiple MYD88-dependent toll-like receptors. Biomaterials. 2021;275:120914. doi:10.1016/j.biomaterials.2021.120914
Recommended Citation
Mao, Chenkai, "In situ vaccination using plant viral particles as a novel approach for cancer immunotherapy" (2022). Dartmouth College Ph.D Dissertations. 88.
https://digitalcommons.dartmouth.edu/dissertations/88
