Enhancing Natural Killer and CD8⁺T Cell-Mediated Anticancer Cytotoxicity and Proliferation of CD8⁺T Cells with HLA-E Monospecific Monoclonal Antibodies

Abstract

Cytotoxic NK/CD8 + T cells interact with MHC-I ligands on tumor cells through either activating or inhibiting receptors. One of the inhibitory receptors is CD94/NKG2A. The NK/CD8 + T cell cytotoxic capability is lost when tumor-associated human leukocyte antigen, HLA-E, binds the CD94/NKG2A receptor, resulting in tumor progression and reduced survival. Failure of cancer patients to respond to natural killer (NK) cell therapies could be due to HLA-E overexpression in tumor tissues. Preventing the inhibitory receptor–ligand interaction by either receptor- or ligand-specific monoclonal antibodies (mAbs) is an innovative passive immunotherapeutic strategy for cancer. Since receptors and ligands can be monomeric or homo- or heterodimeric proteins, the efficacy of mAbs may rely on their ability to distinguish monospecific (private) functional epitopes from nonfunctional common (public) epitopes. We developed monospecific anti-HLA-E mAbs (e.g., TFL-033) that recognize only HLA-E-specific epitopes, but not epitopes shared with other HLA class-I loci as occurs with currently available polyreactive anti-HLA-E mAbs. Interestingly the amino acid sequences in the α1 and α2 helices of HLA-E, critical for the recognition of the mAb TFL-033, are strikingly the same sequences recognized by the CD94/NKG2A inhibitory receptors on NK/CD8 + cells. Such monospecific mAbs can block the CD94/NKG2A interaction with HLA-E to restore NK cell and CD8 + anticancer cell cytotoxicity. Furthermore, the HLA-E monospecific mAbs significantly promoted the proliferation of the CD4 − /CD8 + T cells. These monospecific mAbs are also invaluable for the specific demonstration of HLA-E on tumor biopsies, potentially indicating those tumors most likely to respond to such therapy. Thus, they can be used to enhance passive immunotherapy once phased preclinical studies and clinical trials are completed. On principle, we postulate that NK cell passive immunotherapy should capitalize on both of these features of monospecific HLA-E mAbs, that is, the specific determination HLA-E expression on a particular tumor and the enhancement of NK cell/CD8 + cytotoxicity if HLA-E positive.

HLA-E Binding Peptide as a Potential Therapeutic Candidate for High-Risk Multiple Myeloma

“…As a non-classical major histocompatibility complex (MHC) molecule, HLA-E can interact with NK cells and T cells (15,16). It has been suggested that the overexpression of HLA-E on cells could inhibit the immune clearance function (17). On some tumors, including MM, inflammatory cells and senescent cells with highly expressed HLA-E could escape the NK and T-cell immune surveillance and stay alive in the host body (18)(19)(20)(21).…”

Natural Killer Cells and T Cells in Hepatocellular Carcinoma and Viral Hepatitis: Current Status and Perspectives for Future Immunotherapeutic Approaches

“…These receptors can bind to specific ligands, mainly the major histocompatibility complex class (MHC-1) that is expressed on healthy hepatocytes, which interacts with inhibitory receptors on NK cells and prevents the activation of NK cells. The inhibitory Killer Ig-like receptors (KIRs) that recognize classical MHC-I alleles and the C-type lectin like receptor NKG2A that forms a heterodimer with the CD94 molecule (CD94/NKG2A) and bind HLA-E, a non-classical MHC-I molecule prevent NK cell activation (Figure 1A) [70]. During viral infection, hepatocytes upregulate stimulatory ligands for NK cell activating receptor NKG2D and as a result activation signal surpasses signaling through the inhibitory receptors KIRS and NKG2A, resulting in cytokine release and cytolysis of target cells (Figure 1B).…”

“…NK cells can thus directly eradicate infected cells or tumor cells lacking MHC-1 molecule expression [55]. Therefore, approaches to regulate the balance between activating and inhibitory receptors in NK cells, might also lead to the successful treatment for various liver diseases including HCC [70,72]. Hepatocarcinoma cells express ligands of several activating NK receptors (NKR), including NKp30, natural killer receptor group 2, member D (NKG2D), and DNAM-1, such as the B7 protein homolog 6, the major histocompatibility complex class I chain-related protein A and B (MICA/B), and CD155, respectively, whose expression can correlate with HCC outcome [73,74].…”

The Impact of Inflammation on the Immune Responses to Transplantation: Tolerance or Rejection?

“…Human ECs and several leukocytes, including DCs, express HLA-E on their surface, which is upregulated by proinflammatory cytokines ( 90 , 91 ). HLA-E primarily functions as the specific ligand for an inhibitory receptor (CD94/NKG2A) on NK and CD8+ T cells ( 92 ) ( Figure 1A ). Examining the effects of the presence or absence of HLA-E on the surface of CD94/NKG2A positive NK Cell line (LCL.221-AEH), inhibition of NK cell-mediated cytolysis by HLA-E was documented.…”