CD155 and Its Receptors as Targets for Cancer Therapy

Abstract

CD155, also known as the poliovirus receptor, is an adhesion molecule often overexpressed in tumors of different origins where it promotes cell migration and proliferation. In addition to this pro-tumorigenic function, CD155 plays an immunomodulatory role during tumor progression since it is a ligand for both the activating receptor DNAM-1 and the inhibitory receptor TIGIT, expressed on cytotoxic innate and adaptative lymphocytes. DNAM-1 is a well-recognized receptor involved in anti-tumor immune surveillance. However, in advanced tumor stages, TIGIT is up-regulated and acts as an immune checkpoint receptor, counterbalancing DNAM-1-mediated cancer cell clearance. Pre-clinical studies have proposed the direct targeting of CD155 on tumor cells as well as the enhancement of DNAM-1-mediated anti-tumor functions as promising therapeutic approaches. Moreover, immunotherapeutic use of anti-TIGIT blocking antibody alone or in combined therapy has already been included in clinical trials. The aim of this review is to summarize all these potential therapies, highlighting the still controversial role of CD155 during tumor progression.

Keywords: cancer therapy; poliovirus receptor; tumor immune surveillance.

Figure 1

Schematic structure of human CD155 and its receptors. (A) Human CD155 is produced as four splice variants that differ in the presence of the transmembrane domain (TM) and the length of the C-terminal domain. This latter domain in hCD155α comprises an ITIM domain that initiates inhibitory signals and a domain interacting with clathrin adaptor complex (CID). (B) CD155 receptors include DNAM-1, TIGIT, and CD96 that harbor motifs of potential importance for signaling, as described in the text. Activating domains are depicted in green, whereas inhibitory domains are depicted in red.

Figure 2

Model depicting CD155 roles during tumor progression. On the membrane of cancerous cells, CD155 engagement initiates intracellular signals, leading to proliferation and migration, favoring tumor growth and metastasis. However, in early phases of tumor transformation, CD155 also plays an anti-tumorigenic role, alerting the immune system against cancer. Indeed, it is recognized by DNAM-1 activating receptor expressed on NK and CD8⁺ T cells that mediates tumor cell killing (left). In late phases, DNAM-1 down-modulation from the surface of cytotoxic cells and a concomitant up-regulation of inhibitory CD155 receptors including TIGIT and CD96 contribute to dampen anti-tumor immune responses (right).

Figure 3

Therapeutic approaches targeting CD155 and its receptors. (Left): The direct targeting of CD155-expressing tumors can be achieved using engineered oncolytic polioviruses that result in tumor cell lysis. Dendritic cells (DCs) will capture apoptotic bodies, increasing their capability to present tumor antigens. DCs also express CD155, and they can be directly infected by oncolytic poliovirus. Infection induces type-I interferon production and increases tumor antigen presentation, promoting tumor-specific CD8+ T cell priming. (Right): Anti-tumor immune response may be boosted, potentiating DNAM-1 activation. To this aim, two therapeutic strategies have been exploited to increase tumor cytotoxicity by Natural Killer (NK) and CD8⁺ T lymphocytes (right panel). One is the use of blocking antibodies against the inhibitory receptors TIGIT and CD96 (ICI), allowing the interaction between CD155 and DNAM-1 (upper part of the right panel). This treatment will also prevent CD155 stimulation on DCs, allowing their canonical maturation. As an alternative approach, DNAM-1 can be fused to potent activating cytoplasmic domains to engineer a chimeric antigen receptor (DNAM-1/CAR) able to enhance effector functions of NK or CD8⁺ T cells in adoptive transfer therapies (lower part of the right panel).