Tumor-microenvironment and molecular biology of classic Hodgkin lymphoma in children, adolescents, and young adults

Abstract

Classic Hodgkin lymphoma (cHL) exhibits a bimodal age distribution with incidence peaks in adolescents and young adults (AYAs) aged 15-39 years and in older adults over 50 years. The unique biology of cHL, characterized by a tumor microenvironment (TME) composed predominantly of non-malignant immune and stromal cells, plays a pivotal role in supporting Hodgkin and Reed-Sternberg (HRS) cells, the malignant cells of cHL. Understanding the role of the TME in cHL and its age-related differences is crucial for deciphering differential disease etiologies and developing biomarker-driven targeted therapies. Recent technical advances in single-cell sequencing and multiplexed spatial imaging have revealed age-related differences in TME composition and function, including key cellular interactions, leading to the development of age-specific prognostic indicators. In addition, advances in our ability to isolate nucleic acids from HRS cells have accelerated our understanding of the molecular alterations in cHL, many of which drive interactions within the TME. Molecular differences in cHL between pediatric/AYA and older adult patients have also emerged. This review summarizes the unique biology of cHL and its TME in children, adolescents, and young adults, highlighting recent breakthroughs in our understanding of cHL biology, differences across the age spectrum, and advances in biomarker development.

Keywords: Hodgkin and Reed-Sternberg cells; Hodgkin lymphoma (HL); TME (tumor microenvironment); genetics; pediatric.

Figure 1

Tumor microenvironment ecosystem of cHL according to age groups. cHL presents a bimodal age distribution, with distinct TME characteristics across age groups: Left: cHL age in pediatric patients age <10y: The TME is enriched with M1 macrophages, accompanied by a diverse population of CD4 and CD8 T cells. EBV is more common in this age group and associated with M1 macrophages and cytotoxic T-cells. Center: cHL in AYAs age 15-40y: The TME is associated with M2 macrophages. A subset of AYA HL cases also exhibits LAG3+ type 1 regulatory T cells. Right: cHL in elderly: EBV positivity in HRS cells is more frequently observed in elderly patients and associated with FoxP3 regulatory T-cells. Additionally, the TME is characterized by PD-L1+ macrophages, which are often in close proximity to PD1+ CD4 T cells, indicating a potential immunosuppressive interaction.

Figure 2

Molecular alterations in cHL that contribute to TME. HRS cells can modulate the immune microenvironment to evade tumor clearance by immune cells through several mechanisms: 1) upregulation of PD-L1/L2 leading to inhibition of CD8 T cell activation and proliferation; 2) B2M alterations resulting in MHC class I complex impairment and subsequent immune evasion by CD8 T cells; 3) CIITA alterations leading to MHC class II complex downregulation with subsequent immune evasion by CD4 T cells; and 4) IL-4R gain-of-function mutations causing increased downstream synthesis and release of CCL17, a regulatory T cell attractant.