At the 2026 European Hematology Association (EHA) Annual Meeting, world-renowned lymphoma expert Professor Stephen Ansell from the Mayo Clinic (Rochester, Minnesota, USA) was invited to deliver a keynote speech titled "Deciphering HL biology." Professor Ansell systematically reviewed the molecular origins of Reed-Sternberg (RS) cells in classical Hodgkin lymphoma (cHL), the abnormal activation of key signaling pathways, the complex interactions within the immune microenvironment (TME), and how these biological features drive current immunotherapy strategies while revealing future challenges in drug resistance.01 Tracing the Source: Confirmation of B-cell Lineage and Loss of Identity in RS Cells
Classical Hodgkin lymphoma (cHL) has long been a challenge in pathology. Professor Stephen Ansell recalled that thirty years ago, there was significant controversy regarding the origin of RS cells, with theories suggesting they originated from histiocytes, monocytes, or even as products of infection. With the development of microdissection and sequencing technologies, researchers confirmed that RS cells originate from Germinal Center B-cells by analyzing heavy chain sequences in cHL and associated lymphomas. However, the biological paradox of cHL lies in its “loss of identity.” Data show that RS cells significantly downregulate various transcription factors specific to the B-cell lineage, resulting in a lack of typical B-cell marker expression on their surface. These “functionally crippled” germinal center B-cells should normally be cleared within the germinal center, but through complex genetic mutations and the restarting of signaling pathways, they acquire the ability to survive persistently.
02 Evading Apoptosis: Key Signaling Pathways Driving RS Cell Survival
Professor Ansell conducted an in-depth analysis of how RS cells achieve immortalization through signaling pathway remodeling. Research has found that multiple pathways are highly activated within RS cells, the most core of which include: • NF-κB Pathway: Extensive genetic mutations and continuous activation provide the cells with extremely strong anti-apoptotic capabilities. • JAK-STAT Pathway: 9p24.1 gene amplification not only leads to PD-L1 upregulation but also results in the constitutive activation of the JAK-STAT pathway, as the JAK2 locus is immediately adjacent to PD-L1/L2. • PI3K/AKT Pathway: Further promotes cell proliferation and metabolic remodeling. Additionally, abnormalities in nuclear export proteins such as XPO1 mutations also participate in the antagonism of RS cells against normal immune editing mechanisms in the germinal center.
03 Immune Evasion: MHC Downregulation and High Expression of PD-L1/PD-L2
A hallmark biological feature of cHL is that RS cells account for only a tiny minority of the microenvironment (usually <1%-5%), yet they effectively induce immune suppression. Professor Ansell focused on two major mechanisms of immune evasion:
- MHC Molecule Loss: The majority of cHL cases exhibit downregulation of MHC Class I and Class II molecules, as well as β2-microglobulin (β2M). Data from Professor Margaret Shipp’s team show that only a very small minority of cases retain typical MHC expression, rendering RS cells “invisible” to CD8+ and CD4+ T cells.
- 9p24.1 Amplification and Checkpoint Activation: RS cells almost universally possess 9p24.1 genetic alterations, leading to abnormally high levels of PD-L1 and PD-L2 proteins. These negative signals directly inhibit the effector functions of tumor-infiltrating T cells.
04 Spatial Ecology: Multi-cellular Interactions in the Tumor Microenvironment (TME)
Professor Ansell described the microenvironment of cHL as an “extremely rich and highly ordered ecosystem.” • The “Moat Effect” of Macrophages: Spatial topological studies show that PD-L1-high macrophages form a protective barrier around RS cells, similar to a “moat,” physically blocking the attack of effector T cells. Clinical data indicate that a higher proportion of macrophages in the microenvironment correlates with a worse prognosis for the patient. • T-cell Subset Imbalance: Although a large number of T cells are recruited in cHL, they are predominantly CD4+ T cells rather than CD8+ T cells. These CD4+ T cells mostly exhibit TH1 or Treg phenotypes and highly express exhaustion markers such as LAG-3 and PD-1. • Fibroblasts and Sclerosis: In Nodular Sclerosis Hodgkin Lymphoma (NSHL), fibroblasts not only secrete collagen fibers leading to sclerosis but also interact with RS cells through factors such as PGF-β. Interestingly, general fibroblast infiltration is associated with a better prognosis, but when PGF-β-positive cancer-associated fibroblasts (CAFs) are in close spatial proximity to RS cells, it predicts poorer survival rates.
05 EBV-Positive cHL: A Different Biological Path
Approximately 30% of cHL cases are Epstein-Barr Virus (EBV) positive. Professor Ansell pointed out that EBV plays a “biological surrogate” role in the pathogenesis of cHL. The LMP1 and LMP2A proteins expressed by EBV can mimic CD40 and B-cell receptor (BCR) signals, thereby activating similar survival pathways without the need for genetic mutations. In terms of immunophenotype, EBV-positive cases tend to retain MHC Class I molecules but significantly downregulate MHC Class II molecules, suggesting subtle differences in the mechanisms of response to immunotherapy between EBV-positive and negative cases.
06 Therapeutic Implications: Precision Intervention Guided by Biological Mechanisms
Professor Ansell illustrated how biological characteristics translate into therapeutic advantages through various clinical data, while also pointing out current limitations: • Brentuximab Vedotin (BV) Targeting CD30: The professor emphasized that pure CD30 antibodies (as seen in early studies) had a response rate of only 6%, whereas BV (an antibody-drug conjugate) achieved a 75% response rate by delivering a cytotoxic payload via a “Trojan Horse” approach. The success in cHL lies not in blocking CD30 signals but in utilizing CD30 as a precise delivery target. • “Reverse Signaling” of PD-1 Inhibitors: Nivolumab has shown remarkable efficacy in cHL. Professor Ansell proposed a cutting-edge view: PD-1 blockade not only releases T cells but may also block the “reverse growth-promoting signal” generated within RS cells after the binding of PD-1 to PD-L1 on RS cells, essentially “turning off the growth lights” of RS cells. • Challenges in Cell Therapy: Although CD30 CAR-T and bispecific antibodies (such as AFM13 combined with NK cells) show extremely high response rates in relapsed/refractory patients, due to the powerful inhibitory effect of the TME, the median PFS is currently usually less than 12 months (1 year), and durability remains the greatest pain point.
Conclusion and Outlook Professor Stephen Ansell concluded that cHL is a typical “microenvironment-dependent” tumor. Future research should focus on patients who fail to achieve durable remission after immunotherapy. We need a deeper understanding of why the tumor can still achieve escape through microenvironment remodeling when RS cells are being attacked. Combination therapies, such as JAK inhibitors (e.g., Ruxolitinib) combined with immunotherapy, are expected to further break the deadlock of drug resistance in cHL.
