CTLA-4 and PD-1 Control of T-Cell Motility and Migration: Implications for Tumor Immunotherapy

Abstract

CTLA-4 is a co-receptor on T-cells that controls peripheral tolerance and the development of autoimmunity. Immune check-point blockade (ICB) uses monoclonal antibodies (MAbs) to block the binding of inhibitory receptors (IRs) to their natural ligands. A humanized antibody to CTLA-4 was first approved clinically followed by the use of antibody blockade against PD-1 and its ligand PD-L1. Effective anti-tumor immunity requires the activation of tumor-specific effector T-cells, the blockade of regulatory cells and the migration of T-cells into the tumor. Here, we review data implicating CTLA-4 and PD-1 in the motility of T-cells with a specific reference to the potential exploitation of these pathways for more effective tumor infiltration and eradication.

Keywords: CTLA4; PD1; T-cell; cancer; check-point blockade; immune surveillance; migration; motility.

Figure 1

CD28 and CTLA-4-mediated T-cell motility. T-cell response is initiated in secondary lymphoid organs. Naïve and experienced T-cells enter lymph nodes where they encounter antigen presented by DCs. CTLA-4 limits the interaction of CD4+ T-cells with DCs in the reverse-stop signal model involving an increase in T-cell motility, and a raising of the threshold needed to activate T-cells. In the “reverse-stop signal model”, CTLA-4 induces T-cell motility and limits T-cell binding to DCs during antigen-presentation (1, 2). Reverse stop-signaling might also promote the egress of T-cells as mediated by responses to Sphingosine-1-phosphate (S1P) and chemokines. T-cells then migrate from the vasculature to infected tissue via a combination of chemokines and CTLA-4. CTLA-4 can alter motility by up-regulating key chemokine receptors CCR5 and CCR7 and the sensitivity toward the chemokines (3, 4). In the presence of antibody blockade, T-cells accumulate in the blood and remain circulating in the body (3). Upon entry into tissues, different T-cell subsets play important roles in determining the immune response to infection. The scheme was drawn using pictures from Servier Medical Art.

Figure 2

CTLA-4 regulates T-cell motility. (A) Reverse-stop signal model of CTLA-4 (and PD-1). CTLA-4 induces T-cell motility and limits T-cell binding to DCs during antigen-presentation (1, 2). Agonistic CTLA-4 ligation could directly activate the motility of T-cells and thereby interfere with the dwell times of cells with DCs presenting antigenic peptide. PD-1 can function in a similar way (5). (B) CTLA-4 modulates response to chemokines. Chemokine gradients attract T-cells to the site of injury and inflammation. CTLA-4 can alter motility by up-regulating key chemokine receptors CCR5 and CCR7 and the sensitivity toward the chemokines CCL4 (MIP-1β), CXCL12 (SDF1α) and CCL19, but not CXCL9 (MIG) (3). The scheme was drawn using pictures from Servier Medical Art.

Figure 3

Model where blockade of CTLA-4 and PD-1 enhances migration into tumors and within tumors for more effective tumor rejection. Preventing CTLA-4 engagement, i.e., using anti-CTLA-4-antibodies in vivo modulates the entry and migration of T-cells within tumors for more effective tumor elimination. Anti-CTLA-4 and anti-PD-1 effects on antibodies may also modulate T-cell movement within the tumor mass. (1) (5, 43), (2) (–30, 74), (3) (49), (4) (35, 45), (5) (3, 4, 32), (6) (65, 69), (7) (10, 31, 32), (8) (25, 26, 37, 38). The scheme was drawn using pictures from Servier Medical Art.