Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8+ T-cell function in Hodgkin lymphoma patients

Blood. 2006 Oct 1;108(7):2280-9. doi: 10.1182/blood-2006-04-015164. Epub 2006 Jun 6.

Abstract

In Hodgkin lymphoma (HL), the malignant Hodgkin Reed-Sternberg (HRS) cells constitute only 0.5% of 10% of the diseased tissue. The surrounding cellular infiltrate is enriched with T cells that are hypothesized to modulate antitumor immunity. We show that a marker of regulatory T cells, LAG-3, is strongly expressed on infiltrating lymphocytes present in proximity to HRS cells. Circulating regulatory T cells (CD4+ CD25hi CD45 ROhi, CD4+ CTLA4hi, and CD4+ LAG-3hi were elevated in HL patients with active disease when compared with remission. Longitudinal profiling of EBV-specific CD8+ T-cell responses in 94 HL patients revealed a selective loss of interferon-gamma expression by CD8+ T cells specific for latent membrane proteins 1 and 2 (LMP1/2), irrespective of EBV tissue status. Intratumoral LAG-3 expression was associated with EBV tissue positivity, whereas FOXP3 was linked with neither LAG-3 nor EBV tissue status. The level of LAG-3 and FOXP3 expression on the tumor-infiltrating lymphocytes was coincident with impairment of LMP1/2-specific T-cell function. In vitro pre-exposure of peripheral blood mononuclear cells to HRS cell line supernatant significantly increased the expansion of regulatory T cells and suppressed LMP-specific T-cell responses. Deletion of CD4+ LAG-3+ T cells enhanced LMP-specific reactivity. These findings indicate a pivotal role for regulatory T cells and LAG-3 in the suppression of EBV-specific cell-mediated immunity in HL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antigens, CD / biosynthesis*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / physiology*
  • Child
  • Child, Preschool
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Hodgkin Disease / blood*
  • Hodgkin Disease / metabolism*
  • Humans
  • Lymphocyte Activation Gene 3 Protein
  • Lymphocytes, Tumor-Infiltrating / metabolism*
  • Male
  • Middle Aged
  • Remission Induction
  • Viral Matrix Proteins / metabolism*

Substances

  • Antigens, CD
  • EBV-associated membrane antigen, Epstein-Barr virus
  • Viral Matrix Proteins
  • Lymphocyte Activation Gene 3 Protein
  • Lag3 protein, human