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

Cancer Rep (Hoboken). 2021 Apr;4(2):e1311. doi: 10.1002/cnr2.1311. Epub 2020 Oct 26.

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 Treg 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.

Publication types

  • Review

MeSH terms

  • Adult
  • Age Factors
  • Apoptosis / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Caspase 3 / metabolism
  • Cell Communication / immunology
  • Child
  • Cytokines / metabolism*
  • Epstein-Barr Virus Infections / immunology*
  • Epstein-Barr Virus Infections / microbiology
  • Epstein-Barr Virus Infections / pathology
  • Epstein-Barr Virus Infections / virology
  • Exosomes / metabolism
  • Herpesvirus 4, Human / immunology
  • Hodgkin Disease / immunology*
  • Hodgkin Disease / mortality
  • Hodgkin Disease / pathology
  • Hodgkin Disease / virology
  • Humans
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Prognosis
  • Programmed Cell Death 1 Receptor / metabolism
  • Reed-Sternberg Cells / immunology
  • Reed-Sternberg Cells / pathology*
  • Tumor Escape
  • Tumor Microenvironment / immunology*
  • Tumor-Associated Macrophages / immunology
  • Tumor-Associated Macrophages / metabolism

Substances

  • Cytokines
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • CASP3 protein, human
  • Caspase 3