The overexpression of PCNA by tumor cells strongly correlates with cancer virulence, since PCNA contributes to many survival processes, including DNA replication, DNA repair, and cell-cycle progression.3
Our data suggest that PCNA may additionally promote tumor survival by promoting immune evasion through NKp44-mediated inhibition of NK cell attack. Although PCNA is primarily a nuclear/cytoplasmic factor, other cytoplasmic or nuclear proteins have been shown to serve as ligands to membrane-associated NCRs, notably the NKp30 ligands, CMV-pp65 and nuclear BAT3,4,5
and the NKp46 ligand, vimentin.6
Collectively, these observations suggest that the localization of NCR ligands need not be primarily restricted to the membrane.
We further hypothesize that the PCNA-NKp44 interaction may also contribute to fetal protection from maternal NK cells during pregnancy. Interestingly, PCNA is overexpressed in decidual tissue, and maternal-derived decidual NK cells constitutively express NKp44.7
During the first trimester of pregnancy, these decidual NK cells comprise 50% to 90% of the lymphoid cells in the decidua, and they are tolerized toward the fetal tissue.7
Interestingly, this NK cell tolerance correlates with PCNA overexpression in fetal-derived trophoblast cells during the first trimester.8
Therefore, PCNA-induced inhibition through NKp44 may also contribute to the immune tolerance of maternal NK cells during pregnancy.
Although PCNA has not been previously reported to localize at the plasma membrane, we observed its accumulation at the contact interface with NKp44-expressing NK cells, which is commonly called the NKIS. PCNA was recently shown to interact with the membrane-associated protein, Annexin A2 (ANXA2),9
which was also recently identified as a potential cell surface tumor antigen.10
Although yet untested, we speculate that ANXA2 may play a role in recruiting PCNA to the NKIS upon interaction of a tumor cell with NKp44-expressing NK cells ().
Figure 1. Model of the proposed interaction of NKp44 with PCNA. (1) The interaction with NK cells initiates the movement of PCNA within tumor target cells toward the immunological synapse. PCNA migration within the tumor cell may be initiated (more ...)
To summarize, this work identifies a new ligand for NKp44, demonstrates a novel inhibitory signaling function for NKp44, reveals a previously unrecognized mechanism of immune evasion, and re-emphasizes the role of nuclear proteins as important ligands for NCRs.