2.9 CD96 (TACTILE: T cell activation, increased late expression)
A team of researchers from, Stanford University school of medicine, discovered CD96, an immunoglobulin superfamily  (IgSF) member in 1992 [225]. CD96, also known as T cell activation increased late expression (TACTILE), is an emerging immune checkpoint receptor that plays a significant role in regulating immune responses, particularly in the context of cancer immunotherapy [226]. It is a type I transmembrane glycoprotein expressed on various immune cells, including T cells, natural killer (NK) cells, and subsets of dendritic cells and monocytes [226, 227, 228]. The primary function of CD96 is to modulate immune cell activation and effector functions through its interactions with ligands such as CD155 (Necl5, poliovirus receptor, PVR) [227]. CD155 is expressed on both tumor cells and antigen-presenting cells (APCs), where it acts as a binding partner for CD96, as well as for other immune checkpoint receptors like TIGIT and CD226 (DNAM-1) [229, 230]. CD96 shares similarities with TIGIT in terms of its binding competition with CD226 for CD155 [229]. This competition is crucial in regulating the balance between stimulatory and inhibitory signals that control immune responses. CD226 is an activated receptor on the surface of T and natural killer (NK) cells. In vivo experiments have demonstrated that CD226 mediates the phosphorylation of FOXO1 and activates NK cells through its interaction with CD155-expressing tumor cells [231]. CD112 is usually down regulated in tumor tissue [232]. However, when CD96 binds to CD155, it delivers inhibitory signals that dampen immune cell activation and cytotoxicity, thereby contributing to immune evasion by tumors [233].
In cancer, elevated CD96 expression has been observed on exhausted T cells and dysfunctional NK cells within the TME, correlating with reduced anti-tumor immunity and poorer prognosis [226]. A study by Xu et al. demonstrated that, high infiltration of CD96-positive cells predicted poor prognosis and reduced survival benefits from fluorouracil-based adjuvant chemotherapy in the Zhongshan Hospital (ZSHS) cohort [234]. A study by Sun et al. documented that human CD96 is associated with natural killer cell exhaustion and can predict the prognosis of human hepatocellular carcinoma [235]. The Cancer Genome Atlas (TCGA) data revealed that CD96 expression was notably elevated in high-grade gliomas, isocitrate dehydrogenase (IDH)-wildtype gliomas, and gliomas of the mesenchymal molecular subtype, in a work by Liu et al. [236]. However few study demonstrate that CD96 functions as a co-stimulatory receptor to enhance CD8+ T cell activation and effector responses [237].
Therefore, targeting CD96 presents an attractive strategy to restore immune cell function and enhance anti-tumor responses. Preclinical studies have demonstrated that inhibiting CD96 can lead to enhanced NK cell and T cell activity against tumor cells [226]. Combining CD96 inhibition with other immunotherapies, such as PD-1/PD-L1 inhibitors or TIGIT blockade, holds promise for synergistically enhancing anti-tumor immunity. In three different tumor models, a study demonstrated that co-blockade of CD96 and PD-1 effectively inhibited lung metastases, significantly enhancing local NK cell IFN-γ production and infiltration [238]. A compelling study by Mittal and his team demonstrated that combining anti-CD96 with anti-PD1 and anti-TIGIT therapies yielded superior antitumor responses in various experimental mouse tumor models. These results were observed regardless of the Fc receptor engagement ability of the anti-TIGIT isotype [239]. Clinical trials are underway to evaluate the safety, efficacy, and therapeutic potential of CD96 inhibitors as monotherapy and in combination with other treatments (NCT04446351) (NCT03739710) [240].