Researchers at the University of California, San Diego may now have a clearer understanding of why a particular plant virus effectively activates the immune system to attack cancer cells while other similar viruses do not. The study, published in Cell Biomaterials, details how the cowpea mosaic virus (CPMV) triggers both the innate and adaptive immune pathways, priming the immune system to recognize and fight cancer cells.
“It is fascinating that CPMV, but not other plant viruses, stimulates an anti-tumor response,” said senior author Nicole Steinmetz, PhD, director of nano-ImmunoEngineering at University of California, San Diego.
The new research showed that when CPMV was injected directly into tumors, it triggered a broad immune response drawing neutrophils, macrophages, natural killer cells, and dendritic cells into the tumor microenvironment, while simultaneously activating B cells and T cells to generate long-lasting immune memory, making it a strong candidate for cancer immunotherapy. This activity primes the immune system to recognize and eliminate metastatic tumors as well.
To better understand the mechanism that lead CPMV to have this effect, the research team, led by Steinmetz and first author Anthony Omole, a graduate student in the Steinmetz lab, conducted a side-by-side comparison between CPMV and the closely related cowpea chlorotic mottle virus (CCMV). While both viruses share structural similarities and are taken up at similar rates by human immune cells, their biological effects diverge significantly.
“What we found most exciting is that although human immune cells are not infected by CPMV, they respond to it and are reprogrammed towards an activated state, which ultimately trains them to detect and eradicate cancerous cells,” said Omole.
The data found that CPMV stimulates type I, II, and III interferons, signaling proteins with known anti-cancer properties. In contrast, CCMV induced pro-inflammatory interleukins (IL-22, IL-23, and IL-27) that failed to produce effective tumor clearance. A key finding was that CPMV’s RNA persists longer within immune cells and is delivered to the endolysosome, where it activates Toll-like receptor 7 (TLR7). This receptor is essential for triggering antiviral and anti-tumor responses. CCMV’s RNA did not activate TLR7, which identified a mechanistic basis for CPMV’s immunotherapeutic effects.
The researchers noted that previous work had established CPMV’s ability to elicit both innate and adaptive responses and to protect against tumor rechallenge. In mouse models, tumors injected with CPMV shrank, and in two-tumor models, a systemic response led to shrinkage of distant, untreated tumors. Even RNA-free CPMV virus-like particles (eCPMV) had been shown to trigger immune activity via TLR2 and TLR4, reinforcing the multivalent nature of CPMV’s action.
CPMV had also demonstrated tumor-agnostic efficacy in multiple mouse models as well as in canines with cancer. It had been shown to inhibit tumor-promoting signals and promote long-term immune memory. But CPMV differs from oncolytic viruses in that CPMV does not infect mammalian cells or induce tumor cell lysis and, instead, is recognized as a foreign pathogen through pattern recognition receptors (PRRs), resulting in a cascade of immune activity.
The current study used immune-multiplexing, cellular trafficking assays, and cytokine profiling to probe how CPMV and CCMV differ in immune cell processing and signal transduction. One strength of CPMV is its ability to maintain residence in the tumor microenvironment, facilitating prolonged immune activation. Additionally, its structure presents helper T cell epitopes, adding an adjuvant effect.
While promising, the investigators emphasize that their findings are preclinical, and will require further validation in human systems. They also noted the importance of characterizing systemic effects, determining safety profiles, and selecting the most effective viral constructs for clinical use.
Their study also points to the vast potential of leveraging the breadth of pathogens found not only in mammals and humans for the development of new therapies, but across all life forms.
“The beauty of the mammalian immune system is its ability to recognize pathogen associated molecular patterns (PAMPs) from viruses across different kingdoms—animal viruses, plant viruses, and bacteriophages, etc.—all of which are being repurposed for intratumoral immunotherapy,” the researchers wrote.
As the team looks toward launching early phases of clinical trials, they are refining the formulation, dosage, and treatment protocols.
“The present study provides important insights into the mechanism of action of CPMV. We are diligently working toward the next steps to ensure that the most potent lead candidate is selected to achieve anti-tumor efficacy and safety,” Steinmetz said. “This is the time and we are poised to move this work beyond the bench and toward clinical trials.”
