Background: Classic Hodgkin lymphoma (cHL) remains a biological paradox. A key conceptual puzzle is how the malignant Hodgkin Reed–Sternberg (HRS) cells manage to survive and thrive within a massive tumor microenvironment (TME) dominated by immune cells. Although mechanisms of immune evasion have been extensively explored, the active supportive functions of the TME are less widely recognized. CD4 T cells are particularly intriguing in this context, as they are consistently abundant and form intimate, often rosette‐like contacts with HRS cells. Here, we propose a unifying pathogenetic framework that links these interactions to the origin, evolution, and diagnostic hallmarks of cHL.
Methods: We developed an integrative conceptual framework centered on the interaction between CD4 T cells and HRS cells, based on evidence from in vitro coculture systems, gene expression analyses, immunohistochemistry and established immunology principles.
Results: Our framework highlights that HRS cells produce exceptionally high levels of the chemokine TARC (CCL17), which begins to rise already years before diagnosis and selectively recruits Th2 and regulatory T cells (see figure). The recruited CD4 T cells establish immunological synapses with HRS cells through HLA class II and CD58 mediated interactions. However, the T cells do not become fully activated and the HRS cells deliberately orchestrate a chronic state of intermediate T-cell activation, marked by low-level expression of immune checkpoint molecules and the transcription factor TOX2. Remarkably, this phenotype resembles early commitment toward the T follicular helper (Tfh) lineage which can explain strong support of HRS cells at diagnosis. It also links the cHL immune landscape to the germinal center (GC) niche from which HRS cells arise. Within this niche, GC B cells depend on strong Tfh cell derived survival signals to escape from apoptosis. Disruption of this tightly controlled system may enable the accumulation of genetic aberrations and facilitate the earliest steps of lymphoma development within GCs.
Conclusions: We propose that the core biology of cHL is built on functional units composed of malignant B cells and cooperating CD4 T cells. Within this unit, GC B cells acquire the capacity to recruit and modulate CD4 T cells through TARC production and controlled chronic activation, thereby securing Tfh-like support signals that promote their survival, growth and malignant transformation.
Arjan Diepstra, Yajie Lei, Sophie Teesink, Wouter Plattel, Lydia Visser