Recruitment and Expansion of Tregs Cells in the Tumor Environment-How to Target Them?

Abstract

Regulatory T cells (Tregs) are present in a large majority of solid tumors and are mainly associated with a poor prognosis, as their major function is to inhibit the antitumor immune response contributing to immunosuppression. In this review, we will investigate the mechanisms involved in the recruitment, amplification and stability of Tregs in the tumor microenvironment (TME). We will also review the strategies currently developed to inhibit Tregs' deleterious impact in the TME by either inhibiting their recruitment, blocking their expansion, favoring their plastic transformation into other CD4⁺ T-cell subsets, blocking their suppressive function or depleting them specifically in the TME to avoid severe deleterious effects associated with Treg neutralization/depletion in the periphery and normal tissues.

Keywords: proliferation; recruitment; regulatory T cells; stability; therapeutic targeting; tumor microenvironment.

Figure 1

Chemokine/chemokine receptors axes involved in the recruitment of Tregs in the TME and the major mechanisms involved in the production of these chemokines in the TME. Several chemokine/chemokine receptors contribute to Treg recruitment at a tumor site according to their specific contexts; however, CCR4 and CCR8 appear as the most selectively expressed in TA-Tregs. NK: natural killer cells; MΦ: macrophages; Mo: monocytes; CAF: Cancer associated Fibroblasts.

Figure 2

Evaluation of the chemokine receptor expression in human T-cell subsets in non-small cell lung cancer (NSCLC) and colorectal carcinoma (CRC) single-cell RNA sequencing (scRNA-seq) public datasets. Public scRNA-seq datasets of T cells issued from blood (PBMC), normal adjacent tissue (NAT) and tumor tissues of NSCLC patients (GSE 99254 and SMARTSeq2) [44] and CRC patients (GSE 108989 and SMARTSeq2) [65] were reanalyzed using bioinformatic tools based on the same clusters as described by the authors (pink: Tregs, sky blue: activated CD4⁺ Teff, dark blue: nonactivated CD4⁺ T cells and green: CD8⁺ T cells).

Figure 3

Characterization of cells (immune and nonimmune populations) expressing genes of chemokines in human NSCLC.

Figure 4

The TA-plasmacytoid DC (pDC)/Treg interaction is at the center of the immunosuppressive network in the breast TME. pDC capacity to secrete type-I IFN (IFN-α) is altered by TGF-β produced in the TME. The interaction between pDC and Tregs through ICOS/ICOS-L favors the expansion and survival of Tregs that is amplified by the absence of type-I IFN. These TA-Tregs inhibit the functionality of tumor-infiltrating CD4⁺ and CD8⁺ Teff. Therapeutic strategies with TGFβ-RII antagonists, neutralizing anti-hICOS mAbs, TLR7 or TLR9 agonists or their combination could reduce this immunosuppressive network.