TIGIT and CD96: new checkpoint receptor targets for cancer immunotherapy.

While therapies targeting the co-inhibitory or immune checkpoint receptors PD-1 and CTLA-4 have shown remarkable success in many cancers, not all patients benefit from these therapies. This has catalyzed enormous interest in the targeting of other immune checkpoint receptors. In this regard, TIGIT and CD96 have recently entered the limelight as novel immune checkpoint receptor targets. TIGIT and CD96 together with the co-stimulatory receptor CD226 form a pathway that is analogous to the CD28/CTLA-4 pathway, in which shared ligands and differential receptor:ligand affinities fine-tune the immune response. Although the roles of TIGIT and CD96 as immune checkpoint receptors in T cell and natural killer cell biology are just beginning to be uncovered, accumulating data support the targeting of these receptors for improving anti-tumor immune responses. A clear understanding of the immune cell populations regulated by TIGIT and CD96 is key to the design of immunotherapies that target these receptors in combination with other existing immune checkpoint blockade therapies.

Dougall WC ，Kurtulus S ，Smyth MJ ，Anderson AC ... -  《-》

Molecular Pathways: Targeting CD96 and TIGIT for Cancer Immunotherapy.

Blake SJ ，Dougall WC ，Miles JJ ，Teng MW ，Smyth MJ ... -  《-》

Suppression of Metastases Using a New Lymphocyte Checkpoint Target for Cancer Immunotherapy.

CD96 has recently been shown as a negative regulator of mouse natural killer (NK)-cell activity, with Cd96(-/-)mice displaying hyperresponsive NK cells upon immune challenge. In this study, we have demonstrated that blocking CD96 with a monoclonal antibody inhibited experimental metastases in three different tumor models. The antimetastatic activity of anti-CD96 was dependent on NK cells, CD226 (DNAM-1), and IFNγ, but independent of activating Fc receptors. Anti-CD96 was more effective in combination with anti-CTLA-4, anti-PD-1, or doxorubicin chemotherapy. Blocking CD96 in Tigit(-/-)mice significantly reduced experimental and spontaneous metastases compared with its activity in wild-type mice. Co-blockade of CD96 and PD-1 potently inhibited lung metastases, with the combination increasing local NK-cell IFNγ production and infiltration. Overall, these data demonstrate that blocking CD96 is a new and complementary immunotherapeutic strategy to reduce tumor metastases. This article illustrates the antimetastatic activity and mechanism of action of an anti-CD96 antibody that inhibits the CD96-CD155 interaction and stimulates NK-cell function. Targeting host CD96 is shown to complement surgery and conventional immune checkpoint blockade.

Blake SJ ，Stannard K ，Liu J ，Allen S ，Yong MC ，Mittal D ，Aguilera AR ，Miles JJ ，Lutzky VP ，de Andrade LF ，Martinet L ，Colonna M ，Takeda K ，Kühnel F ，Gurlevik E ，Bernhardt G ，Teng MW ，Smyth MJ ... -  《-》

Targeting Checkpoint Receptors and Molecules for Therapeutic Modulation of Natural Killer Cells.

Kim N ，Kim HS 《Frontiers in Immunology》

Hitting the complexity of the TIGIT-CD96-CD112R-CD226 axis for next-generation cancer immunotherapy.

Jin HS ，Park Y 《-》