Targeting PVR (CD155) and its receptors in anti-tumor therapy

Abstract

Poliovirus receptor (PVR, CD155) has recently been gaining scientific interest as a therapeutic target in the field of tumor immunology due to its prominent endogenous and immune functions. In contrast to healthy tissues, PVR is expressed at high levels in several human malignancies and seems to have protumorigenic and therapeutically attractive properties that are currently being investigated in the field of recombinant oncolytic virotherapy. More intriguingly, PVR participates in a considerable number of immunoregulatory functions through its interactions with activating and inhibitory immune cell receptors. These functions are often modified in the tumor microenvironment, contributing to tumor immunosuppression. Indeed, increasing evidence supports the rationale for developing strategies targeting these interactions, either in terms of checkpoint therapy (i.e., targeting inhibitory receptors) or in adoptive cell therapy, which targets PVR as a tumor marker.

Keywords: PVR; TIGIT; checkpoint; immunotherapy; poliovirus; tumor.

Fig. 1

The multiple faces of the PVR protein. PVR was originally identified as a poliovirus entry receptor that facilitates the attachment and entry of poliovirus into susceptible cells. Replication and translation of the viral genome result in the production of virions that burst from the cell, causing its lysis (lower left panel). Endogenous functions of PVR include cellular adhesion, contact inhibition, cell motility, proliferation, and survival. Many of these PVR functions are achieved by the activation of Ras and RAP1 signaling pathways and require the interactions of PVR with other receptors, such as growth factor receptors (GFR) and integrins in cis, or Nectin-3 (Nec3) in trans (upper right panel). Of particular interest is the immunoregulatory role of PVR (lower right panel) that is accomplished through its interactions with activating and inhibitory immune cell receptors: DNAM-1, TIGIT, and CD96. These complex interactions impact the outcome of the immune response. In addition to transmembrane forms of PVR that perform the functions described above, PVR also exists as a soluble or secreted form (upper left panel). Although this form of PVR is present in many different body fluids and its levels are increased in patients with cancer, its role is still mostly unknown

Fig. 2

Rationale for the development of strategies targeting PVR in tumors. Under physiological conditions (left panel), PVR is expressed at low levels and limited to certain cell types; moreover, a balance between activating and inhibitory signals mediated by PVR maintains the normal function of immune cells. In the tumor microenvironment (right panel), PVR is dramatically overexpressed, suggesting that strategies targeting this protein might be highly selective for tumor cells. In addition, due to its endogenous functions, overexpressed PVR promotes tumor cell invasion, migration, proliferation, and angiogenesis, supporting its therapeutically attractive proto-oncogenic role. Finally, the balance between activating and inhibitory signals is often disturbed in the tumor microenvironment: inhibitory receptors are upregulated and the activating receptor is downregulated, which suggests a prevalence of inhibitory signaling. This phenomenon provides researchers an opportunity to reverse immunosuppression by PVR-targeted inhibition. APC antigen-presenting cell, TILs tumor-infiltrating lymphocytes

Fig. 3

Anti-tumor approaches targeting PVR and its receptors. Several different approaches of anti-tumor therapy based on PVR and its interactions are currently being investigated. One is the direct targeting of tumor cells overexpressing PVR via recombinant oncolytic polioviruses (lower left panel) that productively infect tumor cells, resulting in their lysis and cell death. In addition, the release of tumor antigens and DAMPs from lysed cells, as well as the infection of PVR-expressing antigen-presenting cells, results in the recruitment of other immune cell subsets, enhancing the anti-tumor effect of this approach. Major progress in anti-tumor therapy has also been obtained by targeting PVR checkpoint inhibitors using monoclonal antibodies (lower right panel). By blocking inhibitory interactions, the antibodies reverse immunosupression and increase TIL activation and cytotoxicity, ultimately resulting in the death of tumor cells. Based on accumulating evidence, the blockade of PVR with monoclonal antibodies might exert similar effects on immune cells and their effector capacities, as well as additional immune-independent, anti-tumor mechanisms. An additional potential therapeutic approach targeting PVR might be the use of antibody–drug conjugates (upper left panel), in which a highly potent cytotoxic molecule is complexed to an antibody and delivered to cells by receptor-mediated endocytosis, leading to cell death. The important and potent roles of DNAM-1 in PVR-dependent anti-tumor immune responses, together with the large number of tumors that overexpress PVR provide a strong rationale for the use of DNAM-1 as a chimeric antigen receptor in adoptive cell therapy (upper right panel) designed to enhance effector capacities of these cells and target multiple tumor types. ADCs antibody–drug conjugates, APC antigen-presenting cell, CAR chimeric antigen receptor, DAMP damage-associated molecular pattern, ECD extracellular domain, mAbs monoclonal antibodies, TIL tumor-infiltrating lymphocyte