New strategies to unleash NK cell anti-tumor immunity for cancer immunotherapy

The immune system employs intricate regulatory mechanisms to ensure that immune cells distinguish foreign invaders from healthy tissues via the ‘education’ process. Natural Killer (NK) cell education is of key interest due to its upcoming role in adaptive immunity. In individuals, 13%±6% of the NK cells do not express classical inhibitory receptors as killing inhibitory receptors (KIRs) superfamily and NKG2A. These dysfunctional cells termed ‘anergic’ NK cells, have relatively lowered cytotoxic potential and reduced pro-inflammatory cytokine secretion. Many studies have focused on the role of NK cell education but the molecular framework underlying NK cell anergy or hypo-responsiveness remains unknown. Re-programming these cells and enhancing their functional role have great potential for cancer immunotherapy. Here we decipher the underlying molecular mechanism and identify key intrinsic regulators governing NK cell anergy. Together, reinforced by transcriptome analysis we profile the anergic vs responsive signature. Furthermore, we demonstrate that silencing these intrinsic regulators revokes NK functionality (cytotoxicity. This newfound approach to “reprogram” NK cells in situ via intrinsic regulators is of high clinical relevance for future NK anti-tumor immunotherapeutic approaches.