Semaphorins as Potential Immune Therapeutic Targets for Cancer

Abstract

Semaphorins are a large class of secreted or membrane-bound molecules. It has been reported that semaphorins play important roles in regulating several hallmarks of cancer, including angiogenesis, metastasis, and immune evasion. Semaphorins and their receptors are widely expressed on tumor cells and immune cells. However, the biological role of semaphorins in tumor immune microenvironment is intricate. The dysregulation of semaphorins influences the recruitment and infiltration of immune cells, leading to abnormal anti-tumor effect. Although the underlying mechanisms of semaphorins on regulating tumor-infiltrating immune cell activation and functions are not fully understood, semaphorins can notably be promising immunotherapy targets for cancer.

Keywords: cancer; immune cell; immunotherapy; semaphorins; therapeutic targets; tumor microenvironment.

Figure 1

The classification and structure of semaphorins and their receptors. The upper part: Class 3 semaphorins are secreted proteins. Class 4 to 6 semaphorins are membrane-bound proteins. Sema7A is the only GPI-linked protein in the semaphorin family. The N-terminus of the semaphorins is Sema domain. Adjacent to the downstream area of the Sema domain is the plexin-semaphorin-integrin (PSI) domain. Class 3, 4, and 7 semaphorins contain an immunoglobulin-like domain located downstream to the PSI domain. Class 4 semaphorins have a PDZ binding motif. The lower part: The receptors of semaphorins. The most membrane-bound semaphorins directly bind to conservative plexins, which are classified into four classes A–D. Plexin A proteins are mainly associated with class 5 and 6 semaphorins, whereas Plexin B proteins are mainly associated with class 4 and 5 semaphorins, and Plexin C proteins are bound with Sema7A. Secreted class 3 semaphorins transmit signals requiring neuropilins (Nrps) as coreceptors. Neuropilins are divided into two subtypes, Nrp1 and Nrp2. There are a few semaphorins that require additional interactors to participate in biological activities. Sema4A binds to TIM2, Sema4B binds to CLCP1, Sema4D binds to CD72, and Sema7A binds to integrin β1.

Figure 2

The intricate roles of immune semaphorins and their receptors in tumor microenvironment. Sema3A and Sema3B contribute to decrease in toxicity of CTL by binding to Nrp-1. However, Sema3A promotes M1-Mϕ proliferation but inhibits M2-Mϕ proliferation. Sema4A promotes Treg activation and survival via Nrp1 receptor, but enhance CTL vitality via Plexin-B2 receptor. Sema4D derived from tumor cell or M2-Mϕ promote tumor angiogenesis via Plexin–B1/2 receptor on endothelial cells and inhibit immune response by promoting polarization of MDSCs and inhibiting T-cell function via CD72. Sema4D derived from Mϕ can secrete SDF-1 (CXCL12) that mediates tumor metastasis by binding to CXCR4. Sema7A can mediate macrophages and dendritic cell migration in integrin β1 signals, and mediate tumor lymphatic metastasis through upregulating PDPN expression.

Figure 3

The synergistic anti-tumoral strategies of combination Sema4D mAb with immune checkpoint inhibitors (Nivolumab, PD-1 inhibitor; Ipilimumab, CTLA-4 inhibitor, Pepinemab/VX15/2503, the humanized Sema4D mAb).