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Review
. 2013 Feb;12(2):130-46.
doi: 10.1038/nrd3877.

Advances in targeting cell surface signalling molecules for immune modulation

Sheng Yao  1 , Yuwen Zhu, Lieping Chen
Affiliations
Review

Advances in targeting cell surface signalling molecules for immune modulation

Sheng Yao et al. Nat Rev Drug Discov. 2013 Feb.

Abstract

The past decade has witnessed a surge in the development of immunomodulatory approaches to combat a broad range of human diseases, including cancer, viral infections, autoimmunity and inflammation as well as in the prevention of transplant rejection. Immunomodulatory approaches mostly involve the use of monoclonal antibodies or recombinant fusion proteins that target cell surface signalling molecules on immune cells to drive immune responses towards the desired direction. Advances in our understanding of the human immune system, along with valuable lessons learned from the first generation of therapeutic biologics, are aiding the design of the next generation of immunomodulatory biologics with better therapeutic efficacy, minimized adverse effects and long-lasting clinical benefit. The recent encouraging results from antibodies targeting programmed cell death protein 1 (PD1) and B7 homolog 1 (B7H1; also known as PDL1) for the treatment of various advanced human cancers show that immunomodulatory therapy has come of age.

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Figures

Figure 1
Figure 1. Cell surface signalling molecules as important therapeutic targets
Co-signalling is a complex event that is coordinated through a network of ligand–receptor interactions on the cell surface, with both co-stimulatory and co-inhibitory capacities. The direction and outcome of immune responses are ultimately decided by the interplay of these complicated and often counterbalancing network interactions. Co-signalling pathways are thus important targets for therapeutic intervention. The immunoglobulin (Ig) superfamily and the tumour necrosis factor (TNF)–TNF receptor (TNFR) superfamily are two major gene families of cell surface signalling molecules. Important co-inhibitory receptors that are expressed on lymphocytes include cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death protein 1 (PD1), B- and T lymphocyte attenuator (BTLA), lymphocyte activation gene 3 (LAG3), CD160 and the PD1 homolog (PD1H), whereas CD28, inducible co-stimulator (ICOS), CD137 (also known as 4-1BB), CD27, OX40, glucocorticoid-induced TNFR-related protein (GITR), CD40 ligand (CD40L), B cell activation factor receptor (BAFFR), transmembrane activator and CAML interactor (TACI) and B cell maturation antigen (BCMA) are the main co-stimulatory receptors. Co-signalling ligands, including B7 ligand members and TNF ligands, are mainly expressed by antigen-presenting cells (APCs). APRIL, a proliferation-inducing ligand; B7H1, B7 homolog 1; GITRL, GITR ligand; HVEM, herpesvirus entry mediator; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; ITSM, immunoreceptor tyrosine-based switch motif; MHC, major histocompatibility complex; OX40L, OX40 ligand; PI3K, phosphoinositide 3-kinase; TCR, T cell receptor; TRAF, TNFR-associated factor.
Figure 2
Figure 2. Immune modulation of the priming and the effector phase of lymphocyte activation
a | To promote antigen-specific immune responses during priming in the lymphoid organs, distinctive co-stimulatory pathways can be engaged, such as CD28, CD137 (also known as 4-1BB), CD27, OX40 and CD40, by agonistic reagents or through blockade of the primary early checkpoint receptor cytotoxic T lymphocyte antigen 4 (CTLA4) by an antagonist. Vice versa, the CD28 co-stimulatory pathway can also be blocked by CTLA4–immunoglobulin (Ig) to inhibit T cell activation. b | To expand effector T cells or restore exhausted T cells in the peripheral organs, peripheral inhibitory pathways can be blocked, including the pathway mediated by B7 homolog 1 (B7H1) and programmed cell death protein 1 (PD1), B7H4, lymphocyte activation gene 3 (LAG3) as well as B- and T lymphocyte attenuator (BTLA); alternatively, co-stimulatory receptors on effector T cells — such as CD137 and OX40 — can be activated. mAb, monoclonal antibody.
Figure 3
Figure 3. B7–CD28 family and newly discovered interactions
In addition to known interactions (see Fig. 1), B7 homolog 1 (B7H1) was recently found to interact with and deliver a negative signal through B7.1, which is expressed on activated T cells. Human B7H2 — also known as inducible co-stimulator ligand (ICOSL) — was identified to engage both CD28 and cytotoxic T lymphocyte antigen 4 (CTLA4) to modulate T cell activation in addition to ICOS. APC, antigen-presenting cell.
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