Immune Suppression Markers

Within the tumour microenvironment, tumour cells and proteins can act through multiple pathways to suppress T-cell activation, trigger T-cell exhaustion, or activate regulatory T cells (Tregs).

LAG-3

Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor protein expressed on the cell surface of activated cytotoxic t cells and regulatory T cells. Increased expression of LAG-3 can promote T-cell exhaustion and also suppress the functioning of cytotoxic T-cells through Tregs.

Importance

  • LAG-3 is an immune checkpoint receptor protein expressed on the surface of activated cytotoxic or effector T cells and Tregs.
  • Increased LAG-3 expression can induce T-cell exhaustion and promote Tregs mediated suppression of cytotoxic T cell function.
  • Therefore LAG-3 can assist tumour cells to evade immune system of the body.
  • Coordinated functioning of LAG-3 and PD-1 immune checkpoint receptors, co-expressed in certain tumour cells, can induce much higher T-cell exhaustion or suppress cytotoxic T cell function more than any of them alone.
  • According to preclinical study report, blocking of PD-1 pathway may upregulate LAG-3 to assist in tumour growth.

Tregs

Regulatory T cells (Tregs) are suppressor T cells that modulate immune response by keeping a check on the activation of cytotoxic T cells. Increased infiltration of Tregs into the tumour microenvironment has been found in several types of tumour.

Importance

  • Tregs or suppressor T cells, modulate immune response by controlling the activation of cytotoxic T cells.
  • Tregs maintain self-tolerance towards self-antigens, thus preventing autoimmunity.
  • In different types of tumours, infiltration of Tregs into the tumour microenvironment has been reported.

MDSCs

Myeloid-derived suppressor cells (MDSCs) are immature heterogeneous immune cells belonging to myeloid lineage. The population of MDSCs expand during cancer, infections, chronic inflammation, and traumatic stress to regulate immune response. They are found in different tumours types and their microenvironments and help in suppressing cytotoxic T cell function.

Importance

  • MDSCs are immature heterogeneous myeloid cell population that expands during cancer, infections, chronic inflammation, and traumatic stress to regulate immune responses.
  • Terminally differentiated macrophages and dendritic cells, and monocytes are examples of mononuclear myeloid cells.
  • Terminally differentiated polymorphonuclear neutrophils, eosinophils, basophils, and mast cells are examples of granulocytic myeloid cells.
  • MDSCs are activated in response to strong signals triggered during immune response.
  • Within tumour microenvironment, MDSCs help to suppress cytotoxic T-cell mediated anti-tumour response by promoting T-cell exhaustion and suppressing their function.
  • High infiltration of MDSCs into the tumour microenvironment has been observed in different types of solid tumours, and correlates with poorer prognosis.
  • Reduction of MDSCs may be predictive for clinical response to immunotherapy.

IDO1

Indoleamine 2, 3-dioxygenase-1 (IDO1) is a heme-containing enzyme that is involved in tryptophan metabolism. It promotes the breakdown of tryptophan into immunosuppressive kynurenine in the tumour microenvironment. It is expressed in response to inflammation and supresses the T cell activity. It may be expressed by different cells, including tumour cells.

Importance

  • IDO1 is an enzyme that catalyses the breakdown of tryptophan into immunosuppressive kynurenine.
  • Tryptophan is an essential amino acid and required for cytotoxic T cell functioning.
  • IDO1 may be expressed on different types of cells such as dendritic cells, endothelial cells, stromal, and also tumour cells.
  • Tryptophan catabolism can help tumours evade immune response; thus, tumour cells upregulate IDO1 expression to improve their survival.
  • Increase in IDO1 expression reduces infiltration of cytotoxic T cells into the tumour microenvironment and also increases the recruitment of Tregs.
  • High infiltration of MDSCs into the tumour microenvironment has been observed in different types of solid tumours, and correlates with poorer prognosis.
  • Reduction of MDSCs may be predictive for clinical response to immunotherapy.