*5.7.2.2 HLA-E expressed on cancer cells can directly bind to CD8+ T cells and NK cells and suppress their tumor-killing activity*

Cancer cells lose their cell surface HLA-Ia alleles (HLA-A, HLA-B, and HLA-C) and upregulate the surface expression of HLA-Ib molecules (HLAE, HLA-F, and HLA-G) [57, 82, 119–128]. The upregulation of HLA-E gene expression is correlated with immunolocalization and overexpression of cell surface HLA-E [71, 91, 128–132]. HLA-E gene expression in some cancers [e.g., melanoma] is ranked 19th among overexpressed genes [133]. HLA-E overexpression and loss of HLA-Ia in

#### **Figure 10.**

*Binding of HLA-E to the inhibitory receptors CD94 and NKG2A on both CD8+ CTLs and NKT cells. The structural configuration of the binding of HLA-E and the inhibitory receptors, leading to the arrest of the antitumor activity function of CD8+ and NKT cells. The interaction between HLA-E and the inhibitory receptors involves the binding of amino acids located on the α1 and α2 helices of HLA-E to specific amino acids on CD94 and NKG2A. The amino acid sequences on HLA-E recognized by the inhibitory receptors are unique and specific for HLA-E and they are also recognized by HLA-E monospecific mAbs. The binding involves H-bonding (H), van der Waal forces (vf), and salt linkages (salt) of the amino acids of HLA-E a1 and a2 helices and CD94 and NKG2A inhibitory receptors. (*Modified from Ravindranath et al. Monoclon Antib Immunodiagn Immunother. 2015,34(3):135–53*).*

*Monospecific and Polyreactive Monoclonal Antibodies against Human Leukocyte Antigen-E… DOI: http://dx.doi.org/10.5772/intechopen.95235*

cancer cells are correlated with disease progression and poor prognosis [60, 82, 130, 134]. Disease progression is attributed to the suppression of the tumor-killing activity of CD8+ cytotoxic T lymphocytes (CTLs) and NKT cells.

Cell surface and soluble HLA-E are capable of binding to the inhibitory receptors CD94 and NKG2A on both CTLs (CD3+/CD8+), NK cells (CD2+, CD7+, CD11b+, CD11c+, CD90+, perforin+, & granzyme A+) and NKT cells (plus CD8+) [25, 27, 135, 136]. These cells are capable of destroying tumor cells. These cells interact with MHC-I ligands (HLA-E) on tumor cells through inhibitory receptors. The binding of above mentioned immune cells to HLA-E overexpressed on tumor cells cell surface may explain why the cancer patients failed to respond to NK cell therapies.

Interaction between HLA-E and inhibitory receptors involves the binding of HLA-E specific amino acids located on α1 and α2 helices (**Table 7**) to specific amino acids on CD94 and NKG2A (**Figure 10**) [22, 27, 135, 136]. This specific interaction is attributed to the loss of anti-tumor activity of CD8+ CTLs as well as that of NK or NKT cells [22, 27, 135, 136]. We have used the synthetic peptides of these sequences to ascertain the specific binding affinity of anti-HLA-E mAbs (**Figure 8**). The ability of monospecific anti-HLA-E mAbs to bind at the site of epitopes of CD94 and NKG2A on HLA-E favor the use of the monospecific anti-HLA-E mAbs to mask binding sites of inhibitory receptors on HLA-E. Such blocking of HLA-E may help restore the antitumor efficacy of NK cells and CD8+ T cells that were lost due to the interaction of inhibitory receptors and HLA-E. Possibly humanized monospecific anti-HLA-E may be potentially considered for anti-cancer NK therapy.
