T-regulatory cell (Treg) targeting in immunotherapy
T-regulatory cells (Treg) and Immunotherapy
T-regulatory cells (Treg), suppress an aberrant immune response against self-antigens, and they also suppress anti-tumor immune responses. Infiltration of a large number of Treg cells into tumor tissues is often associated with poor prognosis. There is accumulating evidence that the removal of Treg cells is able to evoke and enhance anti-tumor immune response. However, systemic depletion of Treg cells may concurrently elicit deleterious autoimmunity.
One strategy used at the Integrative Cancer Treatment & Research Center (ICT-RC) for evoking effective tumor immunity without autoimmunity is to specifically target terminally differentiated effector T-regulatory cells because effector Treg cells are the predominant cell type in tumor tissues. Various cell surface molecules, including chemokine receptors such as CCR4, that are specifically expressed by effector T-regulatory cells can be the candidates for depleting effector T-regulatory cells by specific cell-depleting monoclonal antibodies.
In addition, other immunological characteristics of effector T-regulatory cells, such as their high expression of CTLA-4, active proliferation, and apoptosis-prone tendency, can be exploited to control specifically their functions.
For example, anti-CTLA-4 antibody may kill effector Treg cells or attenuate their suppressive activity. By either having either a tumor biopsy and/or tumor tissue analysis, the Treg cells and antigens associated within the tumor itself can be targeted. A combination of T-regulatory cell targeting (e.g., by reducing Treg cells or attenuating their suppressive activity in tumor tissues) with the activation of tumor-specific effector T cells (e.g., by cancer vaccine (dendritic cell) or immune checkpoint blockade) current cancer immunotherapy can be more effective.
Regulatory T Cells
Cancer immunotherapy involving blockade of immune checkpoint molecules, such as CTLA-4 and PD-1, has shown remarkable clinical success across several types of malignancies.
However, a fraction of patients experience disease progression after treatment; thus, exploring resistant mechanisms for immune checkpoint inhibitors and improving their treatment outcome with additional modalities are of great importance. CD4+ regulatory T (Treg ) cells characterized by expression of the master regulatory transcription factor FOXP3 are a highly immune-suppressive subset of CD4+ T cells that maintain immune homeostasis. Several preclinical and clinical studies suggest that Tregcells hamper immune surveillance against cancer in healthy individuals, prevent the development of effective antitumor immunity in tumor-bearing patients, and promote tumor progression. Therefore, targeting Treg cells should be crucial to improving the treatment outcomes of cancer immunotherapy. Several clinical studies directly or indirectly targeting Treg cells in combination with immune checkpoint inhibitors are ongoing or being planned. Understanding the characteristics and roles of Treg cells in cancer settings could make disease-specific Treg -targeted therapy more efficacious and reduce the incidence of immune-related adverse effects mediated by Treg cell inhibition.