NKG2E comprises an immunogenic peptide, derived from an alu-retrotransposon: An attractive novel target for immunotherapeutic approaches

Abstract

Abstract Background Endogenous retroelements are a main source of targetable tumor-specific antigens that have the potential to augment host adaptive antitumor responses. KLRC3 gene encodes for the NKG2E and NKG2H isoforms of NKG2 family of transmembrane receptors. Current data support that NKG2E represents the main protein isoform. Methods Genome, mobilome and molecular evolutionarily analysis were performed through the corresponding tracks of UCSC Genome Browser Database. NKG2E protein expression data were downloaded from the Human Protein Atlas. NetMHCII 2.3 was used to predict MHC class II binding scores. Results In normal tissues, NKG2E protein is scarcely expressed in a rare subset of immune cells in the intestinal tract and lymphoid tissue. Vice versa, in tumor tissues NKG2E expression is detected in > 75% of tumor cells in cases of liver, breast and ovarian cancer as well as in 25-75% of tumor cells in cases of thyroid, stomach and prostate cancer. NKG2E protein is encoded by the long isoform of KLRC3 gene. The last exon of this mRNA is derived via an Alu-element exonization, which provides the last 14 aa of the coding region. Previous analysis showed that the 14 aa Alu-peptide is hydrophobic and impels the intracellular retention of NKG2E protein thereby impeding its function as a transmembrane receptor. A previous study revealed the presence of highly-specific IgG autoantibodies against the Alu-peptide in a disease known to stimulate Alu RNAs overexpression, but not in healthy individuals. The latter signifies not only a high immunogenicity but also that the host is mostly immunologically ignorant rather than tolerant of the Alu-peptide. Accordingly NetMHCII analysis identifies the Alu-peptide as a HLA-DRB1_0103 and -DRB1_1101 high binder. Conclusion NKG2E protein represents an aberrant molecule that is misexpressed in multiple cancers, including immunologically “cold” tumor types. Characterization of the rare immune cells producing the aberrant NKG2E molecule in normal tissues warrants further research. Subsequent studies could inquire into a TCD4-specific TCR usage that would allow for the inoculation of cancer patients with autologous CD4-T cells reactive against the Alu-peptide. Legal entity responsible for the study Spyros I. Papamichos. Funding Has not received any funding. Disclosure The author has declared no conflicts of interest.