John Hunter, PhD
John Hunter, PhD, is vice president and head of Antibody Research and Development for Compugen USA, Inc. He has more than 15 years of scientific research in monoclonal antibody research, genomics, and translational medicine.
Hunter and Maya Kotturi, PhD, the project team leader for Compugen’s TIGIT program, answered key questions about TIGIT as a target for anticancer therapy and the current development of TIGIT-targeting drugs.
OncLive: How does TIGIT act as an immune checkpoint?
Hunter and Kotturi
: TIGIT is a coinhibitory receptor that is highly expressed on effector and regulatory (Treg) CD4+ T cells, effector CD8+ T cells, and natural killer (NK) cells. TIGIT has been shown to attenuate the immune response by (1) direct signaling, (2) inducing ligand signaling, and (3) competition with and disruption of signaling by the costimulatory receptor CD226 (also known as DNAM-1).
TIGIT signaling has been best studied in NK cells, where it has been demonstrated that engagement with its cognate ligand, poliovirus receptor (PVR; also known as CD155) directly suppresses NK cell cytotoxicity through its cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM) domain. Knockout of the TIGIT
gene or antibody blockade of TIGIT/PVR interaction has shown to enhance NK cell killing in vitro, as well as to exacerbate autoimmune diseases in vivo.
In addition to its direct effects on T and NK cells, TIGIT can induce PVR-mediated signaling in dendritic or tumor cells, leading to the increase in production of anti-inflammatory cytokines such as IL-10. In T cells, TIGIT can also inhibit lymphocyte responses by disrupting homodimerization of the costimulatory receptor CD226, and by competing with it for binding to PVR.
More recently, Compugen and others have generated data suggesting that a new check- point inhibitor, PVRIG, is involved with TIGIT in modulating the CD226 pathway to downregulate T-cell response. As we recently demonstrated with our PVRIG-targeted antibody, COM701, combination blockade of TIGIT and PVRIG significantly increases T cell-mediated proinflammatory cytokine production in vitro.
How does TIGIT compare with other immune checkpoints?
There are many parallels in regulation of T-cell–mediated immunity between the CD226/TIGIT-PVR pathway and the well-defined CD28/CTLA-4–CD80/CD86 pathway. Firstly, the expression kinetics of the costimulatory and coinhibitory receptors in these 2 pathways are very similar. The costimulatory receptors CD226 and CD28 are expressed on both naïve and resting T cells, while the expression of TIGIT and CTLA-4 is induced upon lymphocyte activation. Secondly, CD226 and CD28 have a lower affinity to their respective ligands, and are therefore outcompeted by TIGIT and CTLA-4 for ligand binding. Finally, ligand binding by TIGIT and CTLA-4 attenuates T-cell responses.
TIGIT is highly expressed on lymphocytes, including tumor-infiltrating lymphocytes (TILs) and regulatory T cells, that infiltrate different types of tumors. PVR is also broadly expressed in tumors, suggesting that the TIGIT-PVR signaling axis may be a dominant immune escape mechanism for cancer.
Notably, TIGIT expression is tightly correlated with the expression of another important coinhibitory receptor, PD-1. TIGIT and PD-1 are coexpressed on the TILs of numerous human and murine tumors. Unlike TIGIT and CTLA-4, PD-1 inhibition of T-cell response does not involve competition for ligand binding with a costimulatory receptor. Antibody blockade of both TIGIT and PD-1 in preclinical tumor models synergistically induces tumor rejection, thus providing a strong rationale for TIGIT/PD-1 antibody combinations in humans.
How is TIGIT being targeted?
Different types of biological agents are being utilized to target immune checkpoint receptors and/or their ligands. Classically, coinhibitory receptors, such as CTLA-4, PD-1/PD-L1, and TIGIT are targeted with monoclonal antibodies that can block the interaction between the receptor and its ligand, releasing the inhibitory brake on T-cell activation.
In contrast, costimulatory receptors such as OX40, 41BB, and ICOS are targeted by monoclonal antibodies that are agonistic, and that induce signaling by the target molecules. Fc-fusion proteins comprised of the extracellular domains of either coinhibitory or costimulatory molecules are also being tested clinically as cancer therapeutics.