Targeting the right regulatory T-cell population for tumor immunotherapy

Abstract

Regulatory T cells (Tregs) that suppress tumor-specific T cell-mediated immune responses are the subject of an intense wave of investigation. We recently reported that a subset of Tregs, namely effector/memory CD25(low) cells, are responsible for suppressing high avidity tumor-specific T cells in mouse mammary tumors. Here, we discuss additional findings that clarify this mechanism of Treg-mediated immunosuppression.

Figure 1. Cyclophosphamide, not PC61, enhances the therapeutic effect of the neu-vaccine and high-avidity T-cell activity in neu-N mice. (A) PC61 depletes significantly more CD4⁺FOXP3⁺ T cells than cyclophosphamide (Cy) when given with neu-vaccine. The percent of CD4⁺FOXP3⁺ T cells in the tumor draining lymph nodes of neu-N mice challenged with NT2.5 tumor (5x10⁴ cells on day 0) and treated with the neu-vaccine (3x10⁶ cells on day 3) and high-avidity T cells (5x10⁶ cells on day 4) (HV), with the addition of either 100 mg/kg Cy (HCV) or 150 µg/mouse PC61 (HPV) on day 2. * = p < 0.05, ** = p < 0.001. (B) Only Cy combined with high-avidity T cells and neu-vaccine treatment leads to tumor rejection in neu-N mice. Tumor growth in neu-N mice challenged with NT2.5 tumor (5x10⁴ cells) and treated with high-avidity T cells (5x10⁶ cells) and the neu-vaccine (3x10⁶ cells) (HV) with the addition of either 100 mg/kg Cy (HCV), 150 µg/mouse PC61 (HPV), or Cy and PC61 combined (HCPV). ** = p < 0.001. (C) Cy plus neu-vaccine treatment leads to cytokine secretion by high-avidity T cells. High-avidity (Thy1.2) T cells from tumor draining lymph nodes on neu-N mice treated with high-avidity T cells, neu-vaccine, and Cy (HCV) or PC61 (HPV) were tested for their ability to secrete inflammatory cytokines 3 and 5 days after adoptive transfer. (D) Cy, not PC61, treatment leads to increased β1-integrin expression on high-avidity Tcells. High-avidity T cells isolated from tumor draining lymph nodes 3 d after adoptive transfer in neu-N mice treated with HCV, HPV, or HV. (E,F) Cy and PC61 preferentially deplete different subsets of CD25⁺ Tregs. The number of CD4⁺FOXP3⁺CD25^low (E) or CD4⁺FOXP3⁺CD25^high (F) Tregs in the spleen and tumor draining node (TDN) of neu-N mice treated with HCV, HPV, or HV. * = p < 0.05, ** = p < 0.001. All experiments were conducted at least 3 times (3 mice per group) with similar results.