PD-1 and LAG-3 Checkpoint Blockade: Potential Avenues for Therapy in B-Cell Lymphoma

Cells. 2021 May 10;10(5):1152. doi: 10.3390/cells10051152.


The dependence of cancer on an immunotolerant tumor microenvironment (TME) is well established. Immunotherapies that overcome tumor-induced immune suppression have been central to recent advancements in oncology. This is highlighted by the success of agents that interrupt PD-1 mediated immune suppression in a range of cancers. However, while PD-1 blockade has been paradigm-shifting in many malignancies, the majority of cancers show high rates of primary resistance to this approach. This has led to a rapid expansion in therapeutic targeting of other immune checkpoint molecules to provide combination immune checkpoint blockade (ICB), with one such promising approach is blockade of Lymphocyte Activation Gene 3 (LAG-3). Clinically, lymphoproliferative disorders show a wide spectrum of responses to ICB. Specific subtypes including classical Hodgkin lymphoma have demonstrated striking efficacy with anti-PD-1 therapy. Conversely, early trials of ICB have been relatively disappointing in common subtypes of Non-Hodgkin lymphoma. In this review, we describe the TME of common lymphoma subtypes with an emphasis on the role of prominent immune checkpoint molecules PD-1 and LAG3. We will also discuss current clinical evidence for ICB in lymphoma and highlight key areas for further investigation where synergistic dual checkpoint blockade of LAG-3 and PD-1 could be used to overcome ICB resistance.

Keywords: Hodgkin lymphoma; LAG-3; PD-1; diffuse large B cell lymphoma; follicular lymphoma; immune checkpoint blockade; non-Hodgkin lymphoma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antigens, CD / metabolism*
  • Hodgkin Disease / immunology
  • Hodgkin Disease / metabolism*
  • Humans
  • Immune Checkpoint Proteins
  • Immune System
  • Immunotherapy
  • Ligands
  • Lymphocyte Activation Gene 3 Protein
  • Lymphoma, B-Cell / immunology
  • Lymphoma, B-Cell / metabolism*
  • Lymphoma, Large B-Cell, Diffuse / immunology
  • Lymphoma, Large B-Cell, Diffuse / metabolism*
  • Mediastinum / pathology
  • Nervous System
  • Programmed Cell Death 1 Receptor / metabolism*
  • Tumor Microenvironment


  • Antigens, CD
  • Immune Checkpoint Proteins
  • Ligands
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Lymphocyte Activation Gene 3 Protein
  • Lag3 protein, human