A Northwestern Medicine study has uncovered new insights that may aid in understanding and potentially treating one of the most common and aggressive forms of non-Hodgkin lymphoma, according to findings published in Science Advances.
The study described critical differences in B-cell receptor (BCR) types that may influence the progression and treatment of diffuse large B-cell lymphoma and other forms of B-cell leukemia and lymphomas, which affects more than 80,000 Americans each year.
“B-cells, which are responsible for producing antibodies, rely on BCRs for survival and growth. While most research has focused on the IgM variant of BCRs, this study sheds light on the lesser-understood IgG1 variant,” said Vipul Shukla, PhD, assistant professor of Cell and Developmental Biology, who was co-senior author of the study.
“Our lab focuses on understanding the molecular control of B-cell function, which are a key component of the immune system responsible for generating antibodies,” said Shukla, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “Importantly, like normal B-cells, the cancerous B-cells rely on BCRs to fuel their growth, and the current targeted therapies for B-cell cancers are primarily directed towards suppressing BCR signaling. Notably, all that we know about BCR signaling in the context of cancer is linked to the IgM flavor of BCR.”
The study was inspired by a longstanding clinical observation: patients with B-cell lymphomas expressing IgG BCRs tend to have better outcomes than those with IgM BCRs. To investigate this, investigators engineered lymphoma cells to express either IgM or IgG1 BCRs and analyzed their behavior.
The scientists observed that IgG1 BCRs triggered enhanced calcium signaling, which leads to mitochondrial dysfunction and reduced cell survival. However, this effect could be reversed.
“A major finding was that the survival of IgG1 carrying B-cells could be rescued by IL-21, a cytokine produced by helper T-cells, suggesting that IgG1-positive lymphomas may depend more on their tumor microenvironment than on BCR-mediated signaling alone,” said Ashima Shukla, PhD, research assistant professor of Cell and Developmental Biology, a member of the Shukla laboratory and co-senior author of the study. “Clinically, this opens the possibility of using BCR isotypes as biomarkers to predict patient outcomes and treatment strategies for B-cell cancers.”
Looking ahead, Shukla and his team hope to translate these findings into clinical practice.
“We are in active discussions with clinicians at the Lurie Cancer Center to explore how this knowledge can inform patient care and potentially improve treatment options for B-cell malignancies,” Ashima Shukla said.
The study also opens new avenues for research into autoimmune and inflammatory diseases.
“IgG B-cells in cancers, autoimmunity and inflammatory diseases may have unique vulnerabilities that are distinct from IgM expressing B-cells, which we are actively investigating,” Vipul Shukla said.
Rebecca Schmitz, a student in Feinberg’s Medical Scientist Training Program (MSTP), and Rebecca Southern, PhD, a graduate of the Driskill Graduate Program (DGP), were co-first authors of the study.
The study was supported by the National Cancer Institute R00 award (grant ID: CA248835), an R01 (grant ID: AI187142) from the National Institute of Allergy and Infectious Diseases, and institutional startup funds from Northwestern University and the Lurie Cancer Center. Additional support for the work came from National Cancer Institute grant T32 CA009560 and The Leukemia and Lymphoma Society Fellow Award.
