Therapeutic targeting of regulatory T cells in cancer

Abstract

The success of immunotherapy in oncology underscores the vital role of the immune system in cancer development. Regulatory T cells (Tregs) maintain a fine balance between autoimmunity and immune suppression. They have multiple roles in the tumor microenvironment (TME) but act particularly in suppressing T cell activation. This review focuses on the detrimental and sometimes beneficial roles of Tregs in tumors, our current understanding of recruitment and stabilization of Tregs within the TME, and current Treg-targeted therapeutics. Research identifying subpopulations of Tregs and their respective functions and interactions within the complex networks of the TME will be crucial to develop the next generation of immunotherapies. Through these advances, Treg-targeted immunotherapy could have important implications for the future of oncology.

Keywords: immunotherapy; regulatory T cells; tumor microenvironment.

Figure 1.. Treg activation and expansion in the TME.

The TME and its high antigen burden activate and expand Tregs. Intratumoral Tregs orchestrate a complex cellular and molecular network to alter the tumor milieu. Treg contact dependent suppression mechanisms in the TME include cytolysis via perforin and granzyme A/B and transfer of cyclic AMP by membrane gap junctions. Treg contact independent suppression mechanisms include secretion of IL-10, IL-35, and TGF-β; deprivation of IL-2; conversion of extracellular ATP to adenosine by CD39; and expression of CTLA-4 and LAG3. In addition, tumor cells can recruit peripheral Tregs into the TME by chemokines such as CXCL12, CCL17, CCL22 CCL1. Furthermore, metabolic reprogramming modifies Tregs favor of the TME over effector T cells. Treg activation and expansion in the TME can be supported by multiple mechanisms: (1) IL-2, IDO and TGFβ released from tumor cells; (2) alternate metabolic pathway can be activated in intratumoral Tregs; (3) tumor necrosis factor family genes, OX40, GITR and TNFR2 as well as co-stimulatory receptor ICOS can be upregulated in effector intratumoral Tregs and (4) NRP1 can be activated to maintain their suppressive function. Created with BioRender.com.

Figure 2.. Treg targeted anti-tumor therapies.

1. Therapy targeting Treg depletion in the TME includes kinase inhibitors, low-dose cyclophosphamide and anti-CD25; 2. Blocking chemokine receptors CCR4 and CCR8 can halt Treg migration into the TME; 3. Blocking inhibitory receptors such as CTLA-4, TIGIT and LAG3 reduce Treg suppression function and induce Treg depletion. In addition, chemotherapy, radiation therapy and targeted therapies can sensitize tumors to inhibitory receptor blockade therapy; 4. Targeting co-stimulatory signals such as OX40, GITR, ICOS and TNFR2 can enable Tregs to be less suppressive and decrease intratumoral immunosuppression; 5. Blocking Treg derived inhibitory cytokines such as IL-10, IL-35 and TGF-β can dampen Treg suppressive function in the TME; 6. Blocking NRP-1 directly with anti-NRP1 can lead to Treg fragility and IFN-γ secretion; 7. Administration of metformin, IDO inhibitors and A2AR inhibitors can affect Treg metabolism in the TME, resulting in Treg instability and reduction of CTLA4 and IL-10.