The circuitry of the tumor microenvironment in adult and pediatric Hodgkin lymphoma: cellular composition, cytokine profile, EBV, and exosomes

Abstract

Background: Classical Hodgkin lymphoma (cHL) is a unique lymphoid malignancy with a tumor microenvironment (TME) consisting of a small number of neoplastic-Hodgkin and Reed-Sternberg (H-RS) cells (<1%), surrounded by a large number of nonneoplastic infiltrating immune cells (>90%). The TME of cHL critically depends on immune cells to support tumor growth as H-RS cells cannot survive and proliferate in isolation.

Recent findings: Programmed cell death protein 1 (PD-1) ligand expressed on H-RS cells inhibits the clearance of tumor by causing T-cell exhaustion. Nivolumab and pembrolizumab, PD-1 inhibitors, have been proven to be effective in treating adult and pediatric patients with R/R cHL. Tumor-associated macrophages (TAMs) are a central component of TME and are known to cause poor prognosis in adult HL. However, the prognostic impact of CD68+ TAMs in pediatric HL remains ambiguous. EBV modulates the tumor milieu of HL and plays a strategic role in immune escape by enrichment of the TME with T_reg cells and associated immunosuppressive cytokines in adult HL. In contrast, EBV+ pediatric patients have increased infiltration of CD8⁺ T-cells and show a better therapeutic response suggesting viral-related TME is distinct in childhood HL. The role of CASP3 in apoptosis of H-RS cells and its correlation with response prediction in adult and pediatric HL suggest it may serve as a potential biomarker. In cHL, CD30, EBV, and NF-κB signaling employ exosomes for cell-cell communication that triggers the migration capacity of fibroblasts, stimulate to produce proinflammatory cytokines, and help to create a tumor-supportive microenvironment.

Conclusion: The cHL microenvironment is distinct in adult and pediatric HL. Future studies are required to understand the role of interplay between H-RS cells and EBV-associated microenvironment and their clinical outcome. They may present novel therapeutic targets for the development of antilymphoma therapy.

Keywords: EBV; Hodgkin lymphoma; pediatric; tumor microenvironment.

FIGURE 1

Schematic representation of tumor microenvironment in cHL depicting how H‐RS cells are involved in recruitment, immune evasion, and reprograming of various other infiltrating cells. H‐RS cells secrete CXCL10, CCL20, TARC (CCL17), CCL5/RANTES, and CCL22/MDC that attract T _reg cells. H‐RS cells secrete LTα to attract endothelial cells which in turn assist in T‐cell infiltration. On the other side, Th2 lymphocytes cells also get recruited by expressing CD40, CCR3, CCR4, CCR5 receptors to the corresponding ligand produced by H‐RS cells. M2 macrophages are attracted to the tumor microenvironment by H‐RS cells through the secretion of cytokines IL4, IL10, IL13, and MIF thereby promote tumor growth. IL5 and IL9 promote growth and differentiation of eosinophil and mast cells in TME. IL5 levels correlate with tissue eosinophilia commonly seen in cHL. H‐RS cells play a role in immune evasion by expressing PDL1 that binds to PD1 on T‐cells resulting in inhibition of antitumor immunity. The expression of CASP3+ on H‐RS cells leads to apoptosis and correlates with better survival

FIGURE 2

Schematic illustration showing the role of EBV and exosomes in cell–cell communication and in turn leading to HL tumor growth and dissemination. CD30+ exosomes trafficking to fibroblast support HL tumor dissemination. ADAM10 enhances CD30 shedding that interferes with host immune surveillance. EBV modulates the TME resulting in an impaired immune response