As scientists continue technological advances into the largely unexplored genomic terrain of bacteria and viruses, our understanding of how they operate inside cells increases dramatically, delivering better answers to the question: how do we target and treat them when they become toxic?

Dohun Pyeon’s lab studies the Human papillomavirus, or HPV, a highly prevalent and potent human pathogen that causes over 5 percent of all human cancers. Credit: Harvey Seeley

Dohun Pyeon, associate professor in the Department of Microbiology and Molecular Genetics in the  MSU College of Natural Science, believes a better mechanistic understanding of how viruses elude the human immune system will help us outsmart millions of years of viral evolution and treat virus-driven cancers.

Pyeon joined MSU two years ago (under the Global Impact Initiative) from the University of Colorado Anschutz Medical Campus, and his lab’s latest research landed a 5-year, $3 million National Institutes of Health (NIH) R01 grant to investigate cases of head and neck squamous cell carcinoma (HNSCC) driven by the human papillomavirus, or HPV. The research aims to develop novel immunotherapies for cancer patients.

“Many years ago, when I was a college student, I was thinking about how to treat cancer,” Pyeon said. “We needed something cleverer than injecting toxins or drugs that the cancer cell will find a way to manipulate. I thought that our body had an answer to cancer, and it must be the immune response.”

HPV causes more than 5 percent of all human cancers, including nearly all cervical cancers and almost a quarter of HNSCC, which has increased dramatically in recent years.

In previous NIH-supported projects, Pyeon and his collaborators conducted a global gene expression analysis of HNSCC and cervical tissues in various disease stages. They discovered an astonishing change in immune response as the cancer progressed. Over a period of two to three decades, the HPV virus slowly reprogrammed its host cell in a way that made it invisible to the immune system—a process known as DNA methylation.

“The virus slowly shut down gene expression of the signaling protein CXCL14,” Pyeon said. “That is a really clever thing for the virus to do, so we tried to reverse the reprogramming by engineering HPV infected cancer cells to re-express the CXCL14 gene.”

CXCL14, secreted by our skin and just one small part of the human body’s complex and agile immune response, induces a red flag on virus-infected cells marking where the body’s T cells need to attach and clean up. When cells the virus has reprogrammed become cancerous, those cells inherit an invisibility cloak, so to speak, evading detection by the host immune system.

Using mouse models, Pyeon and his team engineered another virus based on a human immunodeficiency virus, or HIV, that would jumpstart CXCL14 expression in vivo. What they found was that the cancer cells were, in fact, flagged and removed by immune cells known as CD8⁺ T cells.

HPV reprograms the tumor microenvironment by decreasing CXCL14 expression to evade host immune surveillance and create an immunosuppressive bubble. In the absence of CXCL14, the tumor on the left can recruit and induce cancer cell migration and metastasis. When CXCL14 expression is restored on the right, CD8+ T cells and NK cells are recruited and kill cancer cells. Credit: Pyeon Lab

The new NIH grant will further Pyeon’s ground-breaking investigations into the mechanisms that enable CXCL14 to induce such extraordinary immune responses. Specifically, he aims to discover how CXCL14 restarts antigen presentation—those red flags—to mediate tumor suppression, how it increases CD8⁺ T cell migration to eliminate cancer cells and how can it be used as a novel immunotherapy.

The immunotherapy era in cancer treatment broke open in 2014 when the FDA approved the first human engineered antibodies known as PD-1 inhibitors. Cancer cells hide by producing large amounts of PD-L1, the ligand of PD-1, in their microenvironment, inducing a kind of cell-wide blackout that leaves our immune system flying blind. The engineered inhibitors reactivate suppressed and exhausted T cells that express PD-1, boosting the body’s immune response.

“The tumor microenvironment is very different than any other place in our body, and one of the most significant and prominent differences is immune suppression,” Pyeon said. “In this grant, we are proposing to use several different combinations of CXCL14 and immune checkpoint inhibitors PD-1 and PD-L1 to develop a viral vector that can deliver drugs or genes directly to the tumor microenvironment and treat the cancer.”

Just as a new wave of antibiotic-resistant bacteria is driving the development of targeted, laser beam treatments for bacteria-driven diseases, Pyeon’s research aims to outsmart viruses and  fight cancer with our own immune system, equipping HIV to trick and treat only the tumor, rather than flooding the body with drugs.

“We want to just focus on the tumor site, so when our virus-based therapies are ready, we plan to inject it directly into the tumor and break the tumor’s immunosuppressive bubble,” Pyeon said. “As a scientist, I have mostly been focusing on scientific discovery, but this time we will be developing something useful for cancer patients, and that translational research is really exciting.”

Via College of Natural Science 

Banner image: The tumor microenvironment, or TME, of a HNSCC patient is visualized by multicolor fluorescence microscopy. The cancer cell nuclei (stained in blue) suppress the infiltration of cancer eliminating T cells, stained in green and red. Killer T cells and regulatory T cells are stained orange and pink, respectively. Credit: Pyeon Lab