The link between cancer and brain function, specifically emotion and motivation is well documented. The connection of immune response to brain tissue is less well understood. Researchers from Cold Spring Harbor Laboratory (CSHL) who study the link between neurobiology and cancer have explored how the immune system responds to cancerous cells and how those same mechanisms may inform understanding of how autoimmune conditions develop.
Their paper entitled, “Ectopic NMDAR expression in cancer unmasks germline-encoded autoimmunity” is published in Nature.
“Patients with autoimmune diseases often experience the condition coming out of nowhere,” said first author Sam Kleeman, PhD, a recent graduate from CSHL. “It may be from the cancer you never knew you had.”
As described in the paper, the connection between cancer response and autoimmune disease in the brain lies with the antibodies deployed to fight cancer, which also have been found in brains with autoimmune conditions.
The team focused specifically on the autoimmune brain disease, anti-NMDA receptor encephalitis (ANRE). In this condition, the immune system attacks proteins in the brain called NMDA receptors, causing psychosis, insomnia, and seizures. Many ANRE patients also have tumors outside of the brain that produce NMDA receptors, linking these disparate diseases.
By tracking antibodies in a mouse model with NMDA receptor-expressing cancer, the researchers were able to verify that mice with strong anti-NMDA receptor antibody responses were able to produce the strongest immune response to tumor development.
While this may be considered positive in response to tumor growth, anti-NMDA receptor antibodies in the brain are associated with ANRE. In mice without cancer, infusing the brain with anti-NMDA receptor antibodies resulted in the mice exhibiting symptoms consistent with ANRE, including elevated body temperatures and seizures.
“This means that the same immune response against a tumor can produce antibodies with completely opposite effects on the brain,” said co-project lead Hiro Furukawa, PhD, a professor at CSHL. “Understanding which antibodies are harmful and which are protective could eventually help us develop treatments that preserve the immune system’s cancer-fighting abilities while preventing neurological damage.”
Using cryogenic electron microscopy (cryo-EM) the researchers were able to further clarify the interaction between NMDA receptors and antibodies. They compared antibody affinity with germline precursor and mature antibodies, developing a map of interactions between residues for NMDA receptor subunits GluN1 and GluN2B. Focusing on two antibodies, SK3D and SK5A, they confirmed binding affinities identified by their cryo-EM maps using B cells from a patient with ANRE.
Combined, these data suggest that understanding the connection between cancer fighting antibodies and those leading to brain disease like ANRE may be helpful to developing therapies for both diseases.
“Our research shows that while cancer remains deeply puzzling, considering the whole-body response to the disease may help us solve biomedical mysteries that have eluded scientists for decades,” said co-project lead, Tobias Janowitz, MD, PhD, an associate professor at CSHL.
“These findings suggest that germline-encoded anti-NMDAR antibodies contribute to immune surveillance but can also trigger autoimmune disease after maturation, revealing a mechanistic trade-off between cancer immunity and neurotoxicity,” wrote the authors.
“With this knowledge, we can now begin carefully designing antibody-based drugs that could one day be used to treat patients with triple-negative breast cancer,” said Janowitz.
