Abstract
The granted European patent EP 2 561 890 describes a procedure for an immunological treatment of cancer. It is based on the principles of the HLA-supported communication of implantation and pregnancy. These principles ensure that the embryo is not rejected by the mother. In pregnancy, the placenta, more specifically the trophoblast, creates an “interface” between the embryo/fetus and the maternal immune system. Trophoblasts do not express the “original” HLA identification of the embryo/fetus (HLA-A to -DQ), but instead show the non-classical HLA groups E, F, and G. During interaction with specific receptors of NK cells (e.g., killer-immunoglobulin-like receptors (KIR)) and lymphocytes (lymphocyte-immunoglobulin-like receptors (LIL-R)), the non-classical HLA groups inhibit these immunocompetent cells outside pregnancy. However, tumors are known to be able to express these non-classical HLA groups and thus make use of an immuno-communication as in pregnancies. If this occurs, the prognosis usually worsens. This patent describes, in a first step, the profiling of the non-classical HLA groups in primary tumor tissue as well as metastases and recurrent tumors. The second step comprises tailored antibody therapies, which is the subject of this patent. In this review, we analyze the underlying mechanisms and describe the currently known differences between HLA-supported communication of implantation and that of tumors.
Highlights
The close similarities between embryos, i.e., trophoblast invasion and the invasive behavior of tumors have long been known and are the subject of many publications, observations, and hypotheses [1,2]
HLA-E interacts with the killer cell lectin-like receptor C1 (KLRC1), known as NKG2A, -B and -C which is expressed by NK cells [48]
The NKG2A receptor together with the NKG2B receptor belongs to the inhibitory receptors within the NK receptor group 2 (NKG2) family, which mediate an inhibitory signal to the NK cell via immunoreceptor tyrosine-based inhibition motifs (ITIMs) [50]
Summary
The close similarities between embryos, i.e., trophoblast invasion and the invasive behavior of tumors have long been known and are the subject of many publications, observations, and hypotheses [1,2]. As well as standard mother-to-embryo constellations, implantation and pregnancy comprise a close cellular “network” of the trophoblast and maternal tissue Due to this special situation, the trophoblast, to maintain pregnancy, expresses the “non-classical” HLA groups in order to escape the maternal immune system. The structure of the protein corresponds to the classic HLA class Ia groups and forms a peptide binding pocket using the α1 and α2 domains. In this classical conformation, HLA-F forms a complex with β2-microglobulin. Besides the different known protein isoforms, proteasome-generated spliced peptides for classical HLA groups have been described, accounting for approximately one-third. Considering the genetic and structural similarities between classical HLA class I genes and HLA-G, further HLA-G peptides and proteins could be generated through this post-transcriptional modification. EVTs further express the isoforms HLA-G2, -G5, and -G6, while the villous trophoblast cells only express the soluble homolog of HLA-G1, i.e., HLA-G5, which is released into the maternal bloodstream [13,45]
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