In a rare but serious complication of cancer, known as anti-Ma2 paraneoplastic neurological syndrome, the body’s own immune system can start attacking the brain, causing rapid-onset memory loss and cognitive deficits. The trigger for this, has to date been largely unknown, but studies in mice by researchers at University of Utah (U of U) Health have found that some tumors can release a protein, PNMA2, that assembles into a virus-like structure which kicks an out-of-control immune reaction that may ultimately damage brain cells. The study findings provide new insights that might help direct future treatment strategies.

Jason Shepherd, PhD, associate professor of neurobiology at University of Utah Health, and colleagues reported on their findings in Cell, in a paper titled “PNMA2 forms immunogenic non-enveloped virus-like capsids associated with paraneoplastic neurological syndrome,” in which they concluded, “These virus-like properties of PNMA2 may underlie some of the neurological symptoms associated with anti-Ma2 paraneoplastic disease.”

Jason Shepherd, PhD, last author on the study.
Jason Shepherd, PhD, last author on the study. [Charlie Ehlert, University of Utah Health]

“The paraneoplastic Ma antigen (PNMA) proteins are associated with cancer-induced paraneoplastic syndromes that present with an autoimmune response and neurological symptoms,” the authors wrote. But why PNMA proteins are associated with this severe autoimmune disease hasn’t been clear.

The swift escalation of symptoms—which can include memory and behavioral changes, loss of coordination, and even seizures—is a hallmark of anti-Ma2 paraneoplastic neurological syndrome, which is itself one of a group of cancer-related neurological syndromes that occur in less than one in 10,000 people with cancer, Shepherd further explained. The precise symptoms of these diseases vary, but all involve rapid immune reactions against the nervous system. “The symptoms come in quickly and can be quite debilitating,” Shepherd added.

Scientists knew that this flare of immunity often targets the PNMA2 protein. “Patients with elevated levels of PNMA1 (Ma1) or PNMA2 (Ma2) autoantibodies experience limbic/brainstem encephalitis and cerebellar degeneration,” they wrote. “These patients often present with solid peripheral tumors that are a potential source of paraneoplastic Ma antigen (PNMA) protein and antibodies to PNMA proteins can be diagnostic of specific cancers.”

But it wasn’t known either why PNMA2 provokes such a strong immune response, or how to prevent it. The authors continued, “… it has remained enigmatic why these proteins are associated with severe autoimmune disorders, but given the severity of disease, it is crucial to gain an understanding of the pathophysiology.” Co-author Stacey L. Clardy, MD, PhD, a neurologist at U of U, added, “We do not understand what is happening at the cellular or molecular level to actually cause the syndrome. Most patients begin to experience these unusual neurologic symptoms before they even know they have a cancer … understanding the mechanism of disease is crucial to developing better treatments.”

The three-dimensional structure of a PNMA2 complex, which can trigger a dangerous immune reaction when released by tumor cells. [Junjie Xu]
The three-dimensional structure of a PNMA2 complex, which can trigger a dangerous immune reaction when released by tumor cells. [Junjie Xu]

To figure out how PNMA2 kick-starts an immune reaction, study first author Junjie Xu, a graduate researcher in neurobiology at U of U Health, examined the protein’s structure using advanced microscopy. The images showed that multiple PNMA2 proteins spontaneously self-organize into 12-sided complexes that bear a striking resemblance to the geometric protein shells of some viruses. “PNMA2 protein self-assembles into virus-like capsids that are released from cells as non-enveloped capsids,” the investigators wrote. “ … we investigated whether putative virus-like properties of PNMA proteins could explain their association with paraneoplastic neurological disorders.”

Junjie Xu, first author on the study. [Junjie Xu]
Junjie Xu, first author on the study. [Junjie Xu]

One of the immune system’s normal functions is to attack viruses, and the researchers found that the virus-like structure of PNMA2 also makes it prone to targeting. Through studies in mice the team demonstrated that immune system only attacked the PNMA2 protein when it was assembled into these virus-like complexes. “ …  mice injected with PNMA2 capsids produce strong autoantibody generation, even without adjuvant,” they wrote. Mice injected with these PNMA2 capsids developed significant deficits in fear learning and memory.” In contrast, injecting into mice mutant PNMA2 proteins that couldn’t form capsids did not elicit autoantibody production, “… indicating that the fully assembled capsid is immunogenic.”

Once activated, the immune system then doesn’t just attack the PNMA2 produced by the cancer. It also targets the parts of the brain that produce PNMA2 normally, including regions involved in memory, learning, and movement. The brain normally has a degree of protection from the immune system, but prior studies have shown that cancer weakens that barrier, leaving the brain especially vulnerable to this immune onslaught.

“This fascinating research illustrates how tumor cells can manipulate their environment,” says Neli Ulrich, PhD, executive director of the Comprehensive Cancer Center at Huntsman Cancer Institute at the University of Utah and a Jon M. and Karen Huntsman Presidential Professor in Cancer Research at the U. “We hope that this innovative transdisciplinary research will positively impact both the lives of cancer patients and of those who experience neurological symptoms.”

Stacey Clardy, MD, PhD, an author on the study.
Stacey Clardy, MD, PhD, an author on the study. [Charlie Ehlert, University of Utah Health]

In future work, the researchers aim to figure out which aspect of the immune response leads to patients’ rapid cognitive decline—the antibodies themselves, immune cells making their way into the brain, or some combination of the two. The team also noted that their studies were in mice, and “ … we do not definitively know whether PNMA2 capsids in humans are responsible for neurological deficits observed in patients with anti-Ma2 paraneoplastic syndrome.” They further pointed out, “Precisely how PNMA2 capsids trigger the immune response will require further in-depth studies and the development of more chronic models, such as tumor implants, may be required to fully recapitulate human neuropathology and symptoms.”

 

Understanding how the immune system causes neurological symptoms may help scientists design targeted treatments, Shepherd noted. “If we show that PNMA2 antibodies are the culprit that really drives the neurological symptoms, you could devise a way to block those antibodies from getting into the brain or mop them up with something as a treatment … If you can alleviate some of those neurological symptoms, it really would be huge.”

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