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].