Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape

Cancer Res. 2012 Feb 15;72(4):917-27. doi: 10.1158/0008-5472.CAN-11-1620. Epub 2011 Dec 20.

Abstract

Inhibitory receptors on immune cells are pivotal regulators of immune escape in cancer. Among these inhibitory receptors, CTLA-4 (targeted clinically by ipilimumab) serves as a dominant off-switch while other receptors such as PD-1 and LAG-3 seem to serve more subtle rheostat functions. However, the extent of synergy and cooperative interactions between inhibitory pathways in cancer remain largely unexplored. Here, we reveal extensive coexpression of PD-1 and LAG-3 on tumor-infiltrating CD4(+) and CD8(+) T cells in three distinct transplantable tumors. Dual anti-LAG-3/anti-PD-1 antibody treatment cured most mice of established tumors that were largely resistant to single antibody treatment. Despite minimal immunopathologic sequelae in PD-1 and LAG-3 single knockout mice, dual knockout mice abrogated self-tolerance with resultant autoimmune infiltrates in multiple organs, leading to eventual lethality. However, Lag3(-/-)Pdcd1(-/-) mice showed markedly increased survival from and clearance of multiple transplantable tumors. Together, these results define a strong synergy between the PD-1 and LAG-3 inhibitory pathways in tolerance to both self and tumor antigens. In addition, they argue strongly that dual blockade of these molecules represents a promising combinatorial strategy for cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / therapeutic use
  • Antigens, CD / immunology
  • Antigens, CD / physiology*
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Line, Tumor
  • Drug Synergism
  • Immune Tolerance / immunology
  • Lymphocyte Activation Gene 3 Protein
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Transplantation
  • Neoplasms, Experimental / immunology*
  • Neoplasms, Experimental / pathology
  • Neoplasms, Experimental / therapy
  • Programmed Cell Death 1 Receptor / immunology
  • Programmed Cell Death 1 Receptor / physiology*
  • Tumor Escape / immunology*

Substances

  • Antibodies
  • Antigens, CD
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Lymphocyte Activation Gene 3 Protein
  • Lag3 protein, mouse