Regulatory T cells in cancer immunotherapy

Abstract

FOXP3-expressing regulatory T (Treg) cells, which suppress aberrant immune response against self-antigens, also suppress anti-tumor immune response. 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 for evoking effective tumor immunity without autoimmunity is to specifically target terminally differentiated effector Treg cells rather than all FOXP3⁺ T 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 Treg cells can be the candidates for depleting effector Treg cells by specific cell-depleting monoclonal antibodies. In addition, other immunological characteristics of effector Treg 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. It is hoped that combination of Treg-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 or immune checkpoint blockade) will make the current cancer immunotherapy more effective.

Figure 1

Treg suppression mechanisms. Treg cells, which scarcely produce IL-2, deprive IL-2 from the surrounding via their high affinity IL-2 receptor, making it unavailable for responder T cells. They also constitutively express CTLA-4, which down-modulates CD80/CD86 expression by antigen-presenting cells (APCs), thus depriving co-stimulatory signal to responder T cells. Treg cells also produce immune-suppressive cytokines such as IL-10, which also down-modulates APC functions. Under this deprivation of co-stimulatory signal, responder T cells with high-affinity TCRs for the presented antigen die by apoptosis, those with intermediate affinity TCRs are rendered anergic, and those with low-affinity TCRs stay dormant. This IL-2/IL-2 receptor-dependent and CTLA-4-dependent mechanism forms a core basis of Treg-mediated suppression in various tissues including cancer.

Figure 2

Functional classification of human FOXP3⁺CD4⁺ T-cell subpopulations in tumor tissue. Human FOXP3⁺ T cells in the peripheral blood and lymph nodes are composed of heterogeneous subpopulations containing suppressive Treg cells (naive and effector Treg cells) and activated non-Treg cells without suppression function. These subpopulations are designated as Fraction (Fr.) I, II, and III for naive Treg (nTreg), effector Treg (eTreg), and non-Treg cells, respectively. CD25 surface marker can be used in the place of FOXP3 because of their correlative expression in humans. Majority of cancers are infiltrated predominantly by effector Treg cells, whereas certain cancers are infiltrated by both effector Treg cells and non-Treg cells. Tumor-infiltrating effector Treg cells predominantly express various cell surface molecules including CTLA-4, CCR4, and PD-1.

Figure 3

Combination and sequence are the key for effective cancer immunotherapy. See text.