Weill Cornell Medicine researchers have defined new transcriptional and functional characteristics of Hodgkin and Reed-Sternberg (HRS) cells in classic Hodgkin lymphoma (cHL), detailing how malignant cells are the result of an arrested stage of B cell development. The research, published Blood Cancer Journal, shows that characteristics of HRS cells are incomplete plasma cell differentiation, robust unfolded protein response (UPR) activation, and coordinated immune evasion mechanisms that influence both T cells and natural killer (NK) cells.
“Hodgkin lymphoma is unique in that the tumor cells don’t form continuous sheets of tumor cells, but they are largely scattered within lymphoid tissues that are not cancerous,” senior author Ethel Cesarman, MD, PhD, pathologist at Weill Cornell Medicine told Inside Precision Medicine. “High proliferation or reduced cell death are not the predominant features of these cells. It is tumor of B cell origin, but unlike normal B cells that develop into plasma cells that produce antibodies but can no longer divide, the tumor cells of Hodgkin lymphoma are stuck in between.”
To define the molecular activity that leads to this arrested state, the researchers analyzed RNA sequencing data from 18 primary cHL tumors, four cHL cell lines, and matched intra-tumoral B cells. They then compared these data with 40 cases of primary mediastinal B cell lymphoma (PMBL).
The resulting data showed that HRS cells lose core B cell identity programs while simultaneously acquiring partial plasma cell-like gene expression. This reflects an “abortive plasma cell differentiation” process in which B cell development begins but is not completed. Normally, germinal center B cells transition into antibody-secreting plasma cells, but in cHL this process is interrupted, and immunoglobulin production is lost.
An important finding of this study was activation of the unfolded protein response (UPR) pathway, which is usually active in plasma cells to help manage the stress of high-volume antibody production. In HRS cells, however, immunoglobulin synthesis is absent. This mismatch appears to place the cells under chronic endoplasmic reticulum stress, which may then be redirected to serve as a survival mechanism.
The study also found that UPR-related genes, including XBP1, ATF6, and particularly PDIA6, were highly expressed in HRS cells. PDIA6 emerged as a potentially specific diagnostic marker. As Cesarman noted in her interview, Hodgkin lymphoma sometimes can be hard to diagnose. “A marker commonly used is CD30, but these may be expressed in other neoplastic and benign conditions, so PDIA6 may be a useful immunohistochemical marker for further differentiation,” she added.
This provides a new framework for understanding the role of UPR activation, which has not been widely implicated in prior models of Hodgkin lymphoma. Historically cHL research has focused on B cell receptor signaling defects, NF-κB activation, and immune checkpoint expression.
The team also noted that HRS cells showed many similarities to plasma cell malignancies such as multiple myeloma, notably their reliance on UPR signaling. However, unlike multiple myeloma, cHL cells fail to complete terminal plasma cell differentiation and do not consistently express CD138 or secrete immunoglobulins, showing that the two malignancies have only a partially shared differentiation trajectory.
The Weill Cornell team also found that immune evasion is another defining feature of cHL. They found evidence of downregulation of SLAM family ligands, including CD48, which are required for NK cell recognition and activation. This loss impairs NK cell-mediated cytotoxicity. The study also found reduced NK cell infiltration in tumor microenvironments. Additionally, HRS cells are known to evade T cell surveillance through antigen presentation defects and checkpoint ligand expression. Together, these findings show cHL mounts a coordinated escape from both innate and adaptive immunity.
The new findings could have implications for clinical care in the future. The identification of UPR dependency presents the opportunity to target proteostasis pathways as a treatment strategy.
“The UPR is a complex pathway, but there have been studies in solid tumors aiming to target it therapeutically, and in the context of multiple myeloma, it has been suggested that proteosomal inhibitors like bortezomib, act in part by leading to the accumulation of unfolded proteins leading to ER stress and eventually apoptosis,” Cesarman said. “While much more work needs to be done to fully characterize the UPR in Hodgkin lymphoma and identify therapeutically actionable aspects of this pathway, our findings point us in the right direction to explore the potential of such an approach.”
Cesarman also noted that while NK cell-based therapies are under development in oncology, the observed downregulation of NK ligands suggests this may not be a viable strategy for therapeutic development.
Future research will now focus on understanding more about how plasma cell differentiation programs become arrested in germinal center B cells, identifying upstream regulators of UPR activation in cHL, and determining whether these stress pathways are required for tumor cell survival. Additional studies are also expected to explore whether restoring immune recognition signals or targeting proteostasis can be combined with existing immune checkpoint therapies.
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