Weill Cornell Medicine researchers have demonstrated for the first time that Hodgkin lymphoma cancer cells taken from patient samples are immune cells undergoing an “identity crisis.” Normally, B cells mature into plasma cells that produce antibodies to fight infection, but in this case, the cells are caught mid-migration. These switch off key functions of B cells but never fully mature into functional plasma cells, instead surviving as malignant Hodgkin lymphoma cells, also called Reed-Sternberg cells.
Hodgkin lymphoma is the most common cancer in young people between the ages of 15 and 19, but it also affects people over the age of 55. It usually causes swollen lymph nodes in the neck, chest, armpits, or groin, and in advanced cases requires chemotherapy and radiation therapy.
The findings, published April 22 in the Blood Cancer Journal, reframe Hodgkin’s lymphoma as a cancer of failed cell development rather than simply uncontrolled growth, and suggest new diagnostic biomarkers to distinguish Hodgkin’s lymphoma from other related non-Hodgkin’s lymphomas.
“Hodgkin lymphoma cells are thought to originate from B cells that are in the process of developing the ability to produce immunoglobulins in germinal centers,” said Dr. Ethel Caesarman, professor of pathology and laboratory medicine and member of the Sandra Edward Meyer Cancer Center at Weill Cornell University, who co-led the study. “In this study, we found that they were on the path to differentiate into plasma cells, and that process was aborted because they could not produce immunoglobulins like normal plasma cells.”
Dr. Lisa Giulino-Ross, chair of the Department of Pediatric Hematology and Oncology at New York University Langonne and previously at Weill Cornell University, co-led the study. Dr. Mikhail Roshal, a pathologist at Memorial Sloan Kettering Cancer Center, and Dr. Isabella Kong, a postdoctoral fellow in the Department of Pediatrics at Weill Cornell University, are lead authors of the paper.
evade the immune system
To understand the origin of Hodgkin lymphoma cells, the research team analyzed gene expression profiles of 18 primary tumors and four cell lines. Researchers compared data from Hodgkin lymphoma and a rare lymphoma called primary mediastinal B-cell lymphoma (PMBL). This lymphoma is associated with B cells and occurs in the same location in the body. The researchers noted that the two lymphomas express different sets of genes, and that Hodgkin lymphoma cells are more similar to multiple myeloma, a plasma cell cancer, than to other lymphomas.
Hodgkin lymphoma cells downregulate some proteins and are no longer like B cells. In addition, they upregulate other proteins to bring them closer to plasma cells, but they do not fully function as plasma cells. ”
Dr. Isabella Kong, Postdoctoral Fellow in Pediatrics, Weill Cornell University
For example, the research team found that genes in the unfolded protein response (UPR) pathway were abnormally active in Hodgkin lymphoma cells.
The UPR helps plasma cells cope with stress by producing large amounts of immunoglobulins to fight infections. Because Hodgkin lymphoma cells cannot produce these antibodies, they are under constant internal tension and may use this stress response as a survival mechanism.
The study also showed a new way for Hodgkin lymphoma cells to evade immune detection. Normally, natural killer (NK) cells, part of the innate immune system, are fast-reacting sentinels that scan cells for specific surface “markers” that signal them to attack. Hodgkin lymphoma cells downregulate a set of markers called SLAM family ligands, including CD48, so NK cells are unable to recognize the tumor as a threat and mount an effective attack. The researchers also found that the number of natural killer cells in the tumor itself was low, suggesting that the cancer cells may be actively eliminating or repelling cancer cells from the tumor site.
These cancer cells also evade T cells, which are part of the adaptive immune response, through other mechanisms, allowing tumors to evade both major means of immune surveillance.
The discovery could lead to new diagnostic markers that can help doctors distinguish Hodgkin lymphoma from other cancers with similar symptoms. For example, the presence of PDIA6 protein may indicate Hodgkin lymphoma. This is because the PDIA6 protein is involved in the UPR and is specifically upregulated in these cells.
“Ultimately, we need better targeted treatments than chemotherapy, which has long-term side effects,” said Dr. Seserman, who is also a pathologist at NewYork-Presbyterian/Weill Cornell Medical Center. “There may be a way to selectively target the UPR to help patients.”
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Reference magazines:
Roshal, M. others. (2026). Hodgkin Lymphoma Transcriptome sequencing of Hodgkin and Reed-Sternberg cells reveals evasion from NK cell recognition and unfolded protein responses. blood cancer journal. DOI: 10.1038/s41408-026-01502-1https://www.nature.com/articles/s41408-026-01502-1
